tuberculosis guidelines.doc

8/21/2019 Tuberculosis Guidelines.doc

http://slidepdf.com/reader/full/tuberculosis-guidelinesdoc 1/160

guidelines

Fourth edition

TreaTmenT of Tuberculosis



Treatment of tuberculosis

GuidelinesFourth edition



WHO Library Cataloguing-in-Publication Data:

Treatment of tuberculosis: guidelines !th ed"

WHO#HT$#T%#&''("!&'

)"*ntitubercular agents administration and dosage" &"Tuberculosis+Pulmonary drug thera,y" ".ational health ,rograms" !"Patient com,liance"/"Guidelines" 0"World Health Organi1ation" 2to, T% De,t"

02%. (34 (& ! )/!34 5.L$ classi6cation: WF 7'8

© World Health Organization 2010

*ll rights reser9ed" Publications of the World Health Organi1ation can be obtained from WHO Press+World Health Organi1ation+ &' *9enue *,,ia+ )&)) Gene9a &3+ 2it1erland 5tel: ;!) && 3() !4/3< e-mail:

boo=orders>ho"int8" ?e@uests for ,ermission to re,roduce or translate WHO ,ublications hetherfor sale or for noncommercial distribution should be addressed to WHO Press+ at the abo9e address

5faA: ;!) && 3() !4'7< e-mail: ,ermissions>ho"int8"

The designations em,loyed and the ,resentation of the material in this ,ublication do not im,ly the

eA,ression of any o,inion hatsoe9er on the ,art of the World Health Organi1ation concerning thelegal status of any country+ territory+ city or area or of its authorities+ or concerning the delimitation of

its frontiers or boundaries" Dotted lines on ma,s re,resent a,,roAimate border lines for hich there maynot yet be full agreement"

The mention of s,eci6c com,anies or of certain manufacturersB ,roducts does not im,ly that they areendorsed or recommended by the World Health Organi1ation in ,reference to others of a similar nature

that are not mentioned" rrors and omissions eAce,ted+ the names of ,ro,rietary ,roducts are distin-guished by initial ca,ital letters"

*ll reasonable ,recautions ha9e been ta=en by the World Health Organi1ation to 9erify the informationcontained in this ,ublication" Hoe9er+ the ,ublished material is being distributed ithout arranty of

any =ind+ either eA,ressed or im,lied" The res,onsibility for the inter,retation and use of the materiallies ith the reader" 0n no e9ent shall the World Health Organi1ation be liable for damages arising from

its use"

Designed by minimum gra,hicsPrinted in "



iii

: :

Contents

*bbre9iations 9ii

*c=noledgements 9iii

Foreord iA

Executive summary 1

1. Introduction 15

)") Cha,ter obEecti9es )/)"& Pur,ose of the guidelines )/

)" Target audience )/

)"! sco,e )/

)"/ Why a ne edition )/

)"7 $ethodology )4

)"3 international standards for Tuberculosis Care &)

)"4 eA,iry date &)2. Case definitions 23

&") Cha,ter obEecti9es &

&"& Pur,oses of de6ning a T% case &

&" Case de6nitions &

&"! *natomical site of T% disease &!

&"/ %acteriological results &/

&"7 History of ,re9ious treatment: ,atient registration grou, &7&"3 Hi status &4

3. Standard treatment regimens 29

") Cha,ter obEecti9es &(

"& *ims of treatment &(

" essential anti-T% drugs &(

"! standard regimens for de6ned ,atient grou,s )

"/ ne ,atients &"7 Pre9iously treated ,atients and multidrug resistance 7

"3 standard regimens for ,re9iously treated ,atients 4

"4 O9erall considerations in selecting a countryBs standard regimens!&



iv

rEamEn o! u"ErCu#oSIS: $uIdE#InES

%. monitoring during treatment 53

!") Cha,ter obEecti9es /

!"& $onitoring the ,atient /

!" *ssessing treatment res,onse in ne and ,re9iously treated ,ulmonary T% ,atients+ and acting on the results /

!"! eAtra,ulmonary T% /3

!"/ ?ecording standardi1ed treatment outcomes /3

!"7 Cohort analysis of treatment outcomes /3

!"3 $anagement of treatment interru,tion /(

!"4 Pre9ention of ad9erse eects of drugs /(

!"( $onitoring and recording ad9erse eects 7'!")' sym,tom-based a,,roach to managing side-eects of anti-T% drugs7'

5. Co&managemento!'I(andactive"disease )5

/") Cha,ter obEecti9es 7/

/"& Hi testing and counselling forall,atients =non or sus,ected to ha9e T%7/

/" Hi ,re9ention in T% ,atients 73

/"! T% treatment in ,eo,le li9ing ith Hi 73

/"/ Co-trimoAa1ole ,re9enti9e thera,y 7(/"7 *ntiretro9iral thera,y 7(

/"3 drug susce,tibility testing 3)

/"4 Patient monitoring during T% treatment 3)

/"( Considerations hen T% is diagnosed in ,eo,le li9ing ith Hi ho arealready recei9ing antiretro9iral thera,y 3&

/")' Hi-related ,re9ention+ treatment+ care and su,,ort 3&

). Su*ervisionand*atientsu**ort +5

7") Cha,ter obEecti9es 3/

7"&?oles of the ,atient+ T% ,rogramme sta+ the community and other ,ro9iders3/

7" su,er9ised treatment 33

7"! using a ,atient-centred a,,roach to care and treatment deli9ery34

7"/ Pre9ention of treatment interru,tion 4'

+. reatment o! drug&resistant tu"ercu#osis ,3

3") Cha,ter obEecti9es 4

3"& Green light Committee initiati9e 4

3" Grou,s of drugs to treat $d?-T% 4!

3"! General ,rinci,les in designing an $d?-T% treatment regimen47



v

3"/ Programmatic strategies for treatment of $d?-T% 47

3"7 selection of the countryBs standard $d?-T% treatment regimen4(

3"3 selection of indi9iduali1ed $d?-T% regimens 4(

3"4 $onitoring the $d?-T% ,atient ()3"( duration of treatment for $d?-T% ()

3")' Treating T% ith resistance ,atterns other than $d? (&

3"))?ecording and re,orting drug-resistant T% cases+ e9aluation of outcomes(&

,. reatment o! extra*u#monary " and o! " in s*ecia# situations 95

4") Cha,ter obEecti9es (/

4"& Treatment of eAtra,ulmonary T% (/

4" im,ortant drug interactions (74"! Treatment regimens in s,ecial situations (3

annexes 1-1

)" essential 6rst-line antituberculosis drugs )'

&" summary of e9idence and considerations underlying the recommendations))/

" T% treatment outcomes ))

!" im,lementation and e9aluation of the fourth edition )/" suggestions for future research )!)

7" $embers of the Guidelines Grou, )!/

ConEnS



vii

*F% acid-fast bacilli

*0D2 ac@uired immunode6ciency syndrome

*?T antiretro9iral thera,y

DOT directly obser9ed treatment

DOT2 the internationally agreed strategy for T% control

D?2 drug resistance sur9eillanceD2T drug susce,tibility testing

ethambutol

PT% eAtra,ulmonary tuberculosis

I* eAternal @uality assurance

FDC 6Aed-dose combination

GLC Green Light Committee

H isonia1idH0 human immunode6ciency 9irus

02TC 0nternational 2tandards for Tuberculosis Care

$D? multidrug resistance

$D?-T% multidrug-resistant tuberculosis

..?T0 non-nucleoside re9erse transcri,tase inhibitor

.?T0 nucleoside re9erse transcri,tase inhibitor

.TP national tuberculosis control ,rogrammePT% ,ulmonary tuberculosis

? rifam,icin

2 stre,tomycin

T% tuberculosis

T%#H0 H0-related T%

JD?-T% eAtensi9ely drug-resistant tuberculosis

K ,yra1inamide

: :

*bbre9iations



viii

The 2to, T% De,artment of the World Health Organi1ation gratefully ac=noledgesthe members of the Guidelines Grou, 5listed in *nneA 78+ including eremiah $uh-

a Cha=aya+ the Chair,erson"

?ichard $en1ies 5$cGill Mni9ersity+ $ontreal+ Canada8+ Naren 2teingart and Phil-li, Ho,eell 5Mni9ersity of California+ 2an Francisco+ M2*8 and *ndre .unn and

Patric= Philli,s 5%ritish $edical ?esearch Council8 led the teams that com,iled+ syn-thesi1ed and e9aluated the e9idence underlying each recommendation"

2u1anne Hill and Holger 2chnemann facilitated the meeting of the GuidelinesGrou,"

Mseful feedbac= as obtained from the Aternal ?e9ie Grou, 5also listed in *n-neA 78"

*dditional feedbac= and su,,ort ere ,ro9ided by the Guidelines ?e9ie Commit-tee 5Chair+ 2u1anne Hill< 2ecretariat+ Faith $cLellan8"

Publication of the guidelines as su,,orted in ,art by a 6nancial contribution fromthe Global Fund to Fight *0D2+ Tuberculosis and $alaria"

The document as ,re,ared by 2arah ?oyce and $algor1ata Gr1ems=a"

Dorris Ortega ,ro9ided secretarial su,,ort"

: :

*c=noledgements



ix

: :

Foreord

The World Health Organi1ationBs 2to, T% De,artment has ,re,ared this fourthedition of Treatment of tuberculosis: guidelines+ adhering fully to the ne WHO ,roc-

ess for e9idence-based guidelines" 2e9eral im,ortant recommendations are being,romoted in this ne edition"

First+ the recommendation to discontinue the regimen based on Eust & months of

rifam,icin 5&H?K#7H8 and change to the regimen based on a full 7 months of rifam,icin 5&H?K#!H?8 ill reduce the number of rela,ses and failures" This illalle9iate ,atient suering resulting from a second e,isode of tuberculosis 5T%8 and

conser9e ,atient and ,rogramme resources"

2econd+ this fourth edition con6rms ,rior WHO recommendations for drug susce,-tibility testing 5D2T8 at the start of thera,y for all ,re9iously treated ,atients" Findingand treating multidrug-resistant T% 5$D?-T%8 in ,re9iously treated ,atients ill

hel, to im,ro9e the 9ery ,oor outcomes in these ,atients" .e recommendationsfor the ,rom,t detection and a,,ro,riate treatment of 5$D?-T%8 cases ill also

im,ro9e access to life-sa9ing care" The retreatment regimen ith 6rst-line drugs5formerly called Category &Q regimen8 is ineecti9e in $D?-T%< it is therefore criti-

cal to detect $D?-T% ,rom,tly so that an eecti9e regimen can be started"

Third+ detecting $D?-T% ill re@uire eA,ansion of D2T ca,acity ithin the conteAtof country-s,eci6c+ com,rehensi9e ,lans for laboratory strengthening" This fourth

edition ,ro9ides guidance for treatment a,,roaches in the light of ad9ances in lab-oratory technology and the countryBs ,rogress in building laboratory ca,acity" 0n

countries that use the ne ra,id molecular-based tests+ D2T results for rifam,icin#

isonia1id ill be a9ailable ithin )R& days and can be used in deciding hich regimenshould be started for the indi9idual ,atient" ?a,id tests eliminate the need to treat in

the dar=Q during the long ait for results of D2T by other methods 5ee=s for li@uidmedia methods or months for solid media methods8"

%ecause of the delays in obtaining results+ this ne edition recommends that coun-tries using con9entional D2T methods should start treatment ith an em,irical regi-

men" 0f there is a high li=elihood of $D?-T%+ em,irical treatment ith an $D?regimen is recommended until D2T results are a9ailable" Drug resistance sur9eil-

lance 5D?28 data or sur9eys ill be re@uired to identify subgrou,s of T% ,atientsith the highest ,re9alence of $D?-T%+ such as those hose ,rior treatment hasfailed" 0m,lementation of these recommendations ill re@uire e9ery country to in-

clude an $D?-T% regimen in its standards for treatment in collaboration ith theGreen Light Committee 0nitiati9e"



x


Fourth+ diagnosing $D?-T% cases among ,re9iously treated ,atients and ,ro9idingeecti9e treatment ill greatly hel, in halting thes,readof $D?-T%" This editionalso addresses the ,re9ention of ac@uired$D?-T%+ es,ecially among ne T% ,atientsho already ha9e isonia1id-resistant$ycobacterium tuberculosishen they start

treatment" The meta-analyses that form the e9idence base for this re9ision re9ealedthat ne ,atients ith isonia1id-resistant T% ha9e a greatly increased ris= of ac@uiring

additional drug resistance" To ,re9ent am,li6cation of eAisting drug resistance+ thisedition includes the o,tion of adding ethambutol to the continuation ,hase of treat-

ment for ne ,atients in ,o,ulations ith high ,re9alence of isonia1id resistance"0n addition+ the daily dosing recommended for the intensi9e ,hase may also hel, in

reducing ac@uired drug resistance+ es,ecially in ,atients ith ,retreatment isonia1idresistance"

Finally+ this edition strongly reaSrms ,rior recommendations for su,er9ised treat-ment+ as ell as the use of 6Aed-dose combinations of anti-T% drugs and ,atient =its

as further measures for ,re9enting the ac@uisition of drug resistance"

Mse of the ne WHO ,rocess for e9idence-based guidelines re9ealed many =ey un-ansered @uestions" What is the best ay to treat isonia1id-resistant T% and ,re-

9ent $D? What is the o,timal duration of T% treatment in H0-,ositi9e ,atientsWhich ,atients are most li=ely to rela,se and ho can they be detected and treated0denti6cation of such crucial @uestions for the future research agenda is an im,ortant

outcome of this re9ision and ill re@uire careful follo-u, to ensure that ansersill be ,ro9ided to further strengthen T% care ,ractices"

*s ne studies hel, to 6ll these ga,s in =noledge+ ne laboratory technology isintroduced+ and ne drugs are disco9ered+ these guidelines ill be u,dated and

re9ised" 0n the meantime+ WHO ,ledges its full su,,ort to hel,ing countries to im-,lement and e9aluate this fourth edition of Treatment of tuberculosis: guidelinesandto use the lessons learnt to im,ro9e access to high-@uality+ life-sa9ing T% care"

Dr $ario ?a9iglione

Director2to, T% De,artment



1

$aEor ,rogress in global tuberculosis 5T%8 control folloed the ides,read im,le-mentation of the DOT2 strategy" The 2to, T% 2trategy+ launched in &''7+ builds u,onand enhances the achie9ements of DOT2" .e obEecti9es include uni9ersal access to,atient-centred treatment and ,rotection of ,o,ulations from T%#H0 and multi-

drug-resistant T% 5$D?-T%8" The 2to, T% 2trategy and the Global Plan to im,le-ment the ne strategy ma=e it necessary to re9ise the third edition of Treatment of

tuberculosis: guidelines for national ,rogrammes+ ,ublished in &''"

Creation of the fourth edition follos ne WHO ,rocedures for guidelines de9elo,-ment" With in,ut from a grou, of eAternal eA,erts the Guidelines Grou, WHO

identi6ed se9en =ey @uestions+ and systematic re9ies ere conducted for each @ues-tion" The Guidelines Grou, based its recommendations on the @uality of the e9idence

5assessed according to the G?*D methodology8+ ,atient 9alues+ and costs+ as ell Eudgements about trade-os beteen bene6ts and harms" ?ecommendations ere

rated as strongQ or conditionalQ"

The e9idence and considerations underlying each recommendation are summari1edin *nneA &"

* strong recommendationis one for hich desirable eects of adherence to the rec-ommendation clearly outeigh the undesirable eects" The strong recommendations

in this edition use the ords shouldQ or should notQ" .o alternati9es are listed"

* conditional recommendationis one for hich the desirable eects of adherence tothe recommendation ,robably outeigh the undesirable eects but the trade-os are

uncertain"

?easons for uncertainty can include:

lac= of high-@uality e9idence to su,,ort the recommendation< limited bene6ts of im,lementing the recommendation< costs not Eusti6ed by the bene6ts< im,recise estimates of bene6t"

* ea= recommendationis one for hich there is insuScient e9idence and it is basedon 6eld a,,lication and eA,ert o,inion" ?ecommendations for hich the @uality of

e9idence as not assessed in line ith the G?*D methodology are not rated"Conditional and ea= recommendations use the ords mayQ" For se9eral of the con-

ditional recommendations+ alternati9es are listed"

: :

eAecuti9e summary



2


The recommendations that address each of the se9en @uestions are listed belo+and also a,,ear in bold teAt in Cha,ter 52tandard treatment regimens8+ Cha,ter !

5$onitoring during treatment8 and Cha,ter / 5Co-management of H0 and acti9e T%8" *reas outside the sco,e of the se9en @uestions+ as ell as the remaining cha,ters+ha9e been u,dated ith current WHO T% ,olicies and recent references but ere

not the subEect of systematic literature re9ies or of ne recommendations by theGuidelines Grou,"

uestion 1. duration o! ri!am*icin in ne/ *atients

2hould ne ,ulmonary T% ,atients be treated ith the 7-month rifam,icin regimen5&H?K#!H?8 or the &-month rifam,icin regimen 5&H?K#7H8

LRecommendation 1.1

New patients with pulmonary T should recei!e a regimen containing " months

o# ri#ampicin$ 2HR%&'(HR

52trong#High grade of e9idence8

?emar= a:?ecommendation )") also a,,lies to eAtra,ulmonary T%+ eAce,t T% of the central ner9ous system+ bone or Eoint for hich some eA,ert grou,s suggest

longer thera,y 5see Cha,ter 48"

?emar= b:WHO recommends that national T% control ,rogrammes ensure that

su,er9ision and su,,ort are ,ro9ided for all T% ,atients in order to achie9e com-,letion of the full course of thera,y"

?emar= c:WHO recommends drug resistance sur9eys 5or sur9eillance8 for moni-toring the im,act of the treatment ,rogramme as ell as for designing standard

regimens"

L Recommendation 1.2

The 2HR%&'"H& treatment regimen should )e phased out


uestion 2. dosing !re0uency in ne/ *atients

When a country selects &H?K#!H?+ should ,atients be treated ith a daily or threetimes ee=ly intensi9e ,hase


Where!er #easi)le* the optimal dosing #re+uency #or new patients with pulmo,

nary T is daily throughout the course o# therapy


There are to alternati9es to ?ecommendation &"):



3

ExECuI(ESummary

L Recommendation 2.1-

New patients with pulmonary T may recei!e a daily intensi!e phase

#ollowed )y a three times weely continuation phase /2HR%&'(HR * pro,3

!ided that each dose is directly o)ser!ed

5Conditional#High and moderate grade of e9idence8


Three times weely dosing throughout therapy /2HR%& '(HR may )e3 3

used as another alternati!e to Recommendation 2.1* pro!ided that e!ery

dose is directly o)ser!ed and the patient is NOT li!ing with H45 or li!ing in

an H45,pre!alent setting


?emar= a: Treatment regimens for T% ,atients li9ing ith H0 or li9ing inH0-,re9alent settings are discussed in ?ecommendation ! and Cha,ter /"

?emar= b:0n terms of dosing fre@uency for H0-negati9e ,atients+ the system-atic re9ie found little e9idence of dierences in failure or rela,se rates ith

daily or three times ee=ly regimens 5see *nneA &8" Hoe9er+ rates of ac@uireddrug resistance ere higher among ,atients recei9ing three times ee=ly dosing

throughout thera,y than among ,atients ho recei9ed daily drug administra-tion throughout treatment" $oreo9er+ in ,atients ith ,retreatment isonia1id

resistance+ three times ee=ly dosing during the intensi9e ,hase as associ-ated ith signi6cantly higher ris=s of failure and ac@uired drug resistance than

daily dosing during the intensi9e ,hase"


New patients with T should not recei!e twice weely dosing #or the #ull course

o# treatment unless this is done in the conte6t o# #ormal research


?emar=: The a9ailable e9idence shoed e@ui9alent eScacy of daily intensi9e-,hase dosing folloed by to times ee=ly continuation ,hase" Hoe9er+ tice

ee=ly dosing is not recommended on o,erational grounds+ since missing onedose means the ,atient recei9es only half the regimen"

uestion 3. Initia# regimen in countries /ith high #eve#s o! isoniaid

resistance

0n countries ith high le9els of isonia1id resistance in ne T% ,atients+ should the

continuation ,hase 5containing isonia1id and rifam,icin8 be changed in the stan-dard treatment of all ne ,atients+ in order to ,re9ent the de9elo,ment of multidrugresistance)

) This @uestion a,,lies to countries here isonia1id susce,tibility testing in ne ,atients is not done 5orresults are not a9ailable8 before the continuation ,hase begins"



%


L Recommendation 3

4n populations with nown or suspected high le!els o# isoniazid resistance* new

T patients may recei!e HR& as therapy in the continuation phase as an accept,

a)le alternati!e to HR

5Wea=#0nsuScient e9idence+ eA,ert o,inion8

?emar= a:While there is a ,ressing need to ,re9ent multidrug resistance 5$D?8+the most eecti9e regimen for the treatment of isonia1id-resistant T% is not =non"

There is inade@uate e9idence to @uantify the ability of ethambutol to ,rotectrifam,icinQ in ,atients ith ,retreatment isonia1id resistance" The e9idence for

ocular toAicity from ethambutol as not systematically re9ieed for this re9ision+but the ris= of ,ermanent blindness eAists" Thus+ further research 5see *nneA /8 is

urgently needed to de6ne the le9el of isonia1id resistance that ould arrant theaddition of ethambutol 5or other drugs8 to the continuation ,hase of the standardne ,atient regimen in T% ,rogrammes here isonia1id drug susce,tibility test-

ing is not done 5or results are una9ailable8 before the continuation ,hase begins"

?emar= b:Daily 5rather than three times ee=ly8 intensi9e-,hase dosing may alsohel, ,re9ent ac@uired drug resistance in T% ,atients starting treatment ith iso-

nia1id resistance" The systematic re9ie 5*nneA &8 found that ,atients ith isoni-a1id resistance treated ith a three times ee=ly intensi9e ,hase had signi6cantly

higher ris=s of failure and ac@uired drug resistance than those treated ith dailydosing during the intensi9e ,hase"

uestion %. " treatment in *ersons #iving /ith 'I(

2hould intermittent regimens be used for ,ersons li9ing ith H0 What should bethe duration of T% treatment in ,eo,le li9ing ith H0

?emar=:Current WHO recommendations ,romoting the use of antiretro9iral thera-,y in T% ,atients li9ing ith H0 should be ,ut ra,idly into ,ractice"

L Recommendation (.1T patients with nown positi!e H45 status and all T patients li!ing in H45,

pre!alent settings should recei!e daily T treatment at least during the inten,

si!e phase


?emar=:H0-,re9alent settings are de6ned as countries+ subnational administra-ti9e units+ or selected facilities here the H0 ,re9alence among adult ,regnant

omen is U)V or among T% ,atients is V"

L Recommendation (.2

7or the continuation phase* the optimal dosing #re+uency is also daily #or these

patients




5


4# a daily continuation phase is not possi)le #or these patients* threetimesweely dosing during the continuation phase is an accepta)le alternati!e

5Conditional#High and moderate grade of e9idence8L Recommendation (.(

0t is recommended that T% ,atients ho are li9ing ith H0 should recei9e at leastthe same duration of T% treatment as H0-negati9e T% ,atients


?emar= a:2ome eA,erts recommend ,rolonging T% treatment in ,ersons li9ingith H0 5see Cha,ter /8"

?emar= b:Pre9iously treated T% ,atients ho are li9ing ith H0 should recei9ethe same retreatment regimens as H0-negati9e T% ,atients"

?ecommendations )! 5as they relate to ne ,atients8 are summari1ed in Table *belo+ and shon in Tables "& and " in Cha,ter "

Table A STAndArd regimen And doSing frequency for new TB pATienTS

Intensive *hase Continuation *hase Comments

2 months of HrZe a 4 months of Hr

2 months of HrZe 4 months of Hre Applies only in countries with high levels of

isoniaid resistance in new TB patients! and

where isoniaid drug susceptibility testing

in new patients is not done "or results are

unavailable# before the continuation phase

begins

a wHo no longer recommends omission of ethambutol during the intensive phase of treatment for

patients with non$cavitary! smear$negative pulmonary TB or e%trapulmonary disease who are &nown

to be Hi'$negative(

dosing !re0uencyComments

Intensive *hase Continuation *hase

daily daily optimal

daily ) times per wee& Acceptable alternative for any new TB patient

receiving directly observed therapy

) times per wee& ) times per wee& Acceptable alternative provided that the

patient is receiving directly observed therapy

and is noT living with Hi' or living in an Hi'$

prevalent setting "see chapter *#

Note+ daily "rather than three times wee&ly# intensive$phase dosing may help to prevent acquired drug

resistance in TB patients starting treatment with isoniaid resistance "see Anne% 2#(

ExECuI(ESummary



)


uestion 5. S*utum monitoring during " treatment o! smear&*ositive

*u#monary " *atients

0n ,ulmonary T% ,atients ho are initially smear ,ositi9e+ ho eecti9e is moni-

toring s,utum s,ecimens for ,redicting rela,se+ failure and ,retreatment isonia1idresistance

Figures !") and !"& in Cha,ter ! illustrate ?ecommendations /")/""


7or smear,positi!e pulmonary T patients treated with 9rst,line drugs* sputum

smear microscopy may )e per#ormed at completion o# the intensi!ephase o# treatment


?emar= a: This recommendation a,,lies both to ne ,atients treated ith regimenscontaining 7 months of rifam,icin+ and to ,atients returning after default or rela,se

and no recei9ing the 4-month retreatment regimen 5&H?K2#)H?K#/H?8".ote that the end of the intensi9e ,hase may be at & months or months+ de,end-

ing on the regimen"

?emar= b:*9ailable e9idence shoed that smear status at the end of the intensi9e,hase is a ,oor ,redictor of rela,se+ failure and ,retreatment isonia1id resistance"

.onetheless+ WHO continues to recommend ,erforming smear microsco,y atthis stage because a ,ositi9e smear should trigger an assessment of the ,atient+as ell as additional s,utum monitoring 5see ?ecommendations /"& and /"8"

2,utum smear con9ersion at the end of the intensi9e ,hase is also an indicator of T% ,rogramme ,erformance"


4n new patients* i# the specimen o)tained at the end o# the intensi!ephasemonth 2 is smear,positi!e* sputum smear microscopy should )e o)tained at

the end o# the third month



4n new patients* i# the specimen o)tained at the end o# month 3 is smear,positi!e*sputum culture and drug suscepti)ility testing :;T should )e per#ormed


?emar=:.ational T% control ,rogrammes 5.TPs8 should continue to follothe current WHO recommendation to obtain s,utum s,ecimens for smear mi-

crosco,y at the end of months / and 7 for all ne ,ulmonary T% ,atients hoere smear-,ositi9e at the start of treatment" Patients hose s,utum smears are

,ositi9e at month / or 7 5or ho are found to harbour $D?-T% strains at any



+

time8 ill be re-registered as ha9ing failed treatment and be treated according to?ecommendation 3 belo"

L Recommendation 8.(

4n pre!iously treated patients* i# the specimen o)tained at the end o# the inten,si!e phase month 3 is smear,positi!e* sputum culture and drug suscepti)ility

testing :;T should )e per#ormed


uestion ). reatment extension in ne/ *u#monary " *atients

0n ne ,ulmonary T% ,atients+ ho eecti9e is eAtension of treatment for ,re9entingfailure or rela,se

L Recommendation "

4n patients treated with the regimen containing ri#ampicin throughout treat,

ment* i# a positi!e sputum smear is #ound at completion o# the intensi!e phase*

the e6tension o# the intensi!e phase is not recommended


?emar=:WHO recommends that a ,ositi9e s,utum smear at com,letion of theintensi9e ,hase should trigger a careful re9ie of the @uality of ,atient su,,ort

and su,er9ision+ ith ,rom,t inter9ention if needed 5see Cha,ter !8" 0t should alsotrigger additional s,utum monitoring+ as ,er ?ecommendations /"&+ /" and /"!"

uestion +. revious#y treated *atients

Which 5if any8 grou,s of ,atients should recei9e a retreatment regimen ith 6rst-linedrugs

Table "/ in Cha,ter shos ?ecommendations 3")3"!"

L Recommendation <.1

;pecimens #or culture and drug suscepti)ility testing :;T should )e o)tained#rom all pre!iously treated T patients at or )e#ore the start o# treatment. :;T

should )e per#ormed #or at least isoniazid and ri#ampicin

?emar= a:D2T may be carried out by ra,id molecular-based methods or by con-9entional methods" 2,utum should be obtained+ as ell as a,,ro,riate s,ecimens

for eAtra,ulmonary T%+ de,ending on the site of disease"

?emar= b:Obtaining s,ecimens for culture and D2T should not delay the start of treatment" m,irical thera,y should be started ,rom,tly+ es,ecially if the ,atient

is seriously ill or the disease is ,rogressing ra,idly"

ExECuI(ESummary



,



4n settings where rapid molecular,)ased :;T is a!aila)le* the resultsshould guide the choice o# regimen

L Recommendation <.34n settings where rapid molecular,)ased :;T results are not routinely a!aila)le

to guide the management o# indi!idual patients* empirical treatment should )e1

started as #ollows$

L Recommendation <.3.1

T patients whose treatment hasfailed2or other patient groups with high

lielihood o# multidrug,resistant T =:R,T should )e started on an em,

pirical =:R regimen

?emar= a:0n the absence of culture and D2T results+ the ,atient should be clini-cally e9aluated before the $D? regimen is administered"

?emar= b:Other eAam,les of ,atients ith high li=elihood of $D?-T% arethose rela,sing or defaulting after their second or subse@uent course of treat-

ment" 2ee also section "4"&"


T patients returning a#ter de#aulting or relapsing #rom their 9rst treat,

ment course may recei!e the retreatment regimen containing 9rst,line drugs

2HR%&;'1HR%&'8HR& i# country,speci9c data show low or medium le!els

o# =:R in these patients or i# such data are una!aila)le

?emar=:When D2T results become a9ailable+ regimens should be adEusteda,,ro,riately"

L Recommendation <.(

4n settings where :;T results are not yet routinely a!aila)le to guide the man,

agement o# indi!idual patients* the empirical regimens will continue through,

out the course o# treatment


National T control programmes should o)tain and use their country,speci9c

drug resistance data on #ailure* relapse and de#ault patient groups todeterminethe le!els o# =:R.

)0n these guidelines+ em,irical means ,ro9iding treatment before 5or ithout8 =noing hether the

,atientBs T% organisms are $D? or not"&Failures in a ell-run .TP should be infre@uent in the absence of $D?-T%" 0f they do occur+ they aredue either to $D?-T% or to ,rogramme factors such as ,oor DOT or ,oor drug @uality" 0f drug resis-

tance data from failure ,atients are a9ailable and sho lo or medium le9els of $D?+ ,atients shouldrecei9e the retreatment regimen outlined in section 3""&"+ and e9ery eort should be made to address

the underlying ,rogrammatic issues"



9

?emar=:Country-s,eci6c drug resistance data should include data strati6ed byty,e of regimen gi9en for the ,atientBs 6rst course of T% treatment 5i"e" & 9s 7

months of rifam,icin8"

Table % belo lists =ey changes in this fourth edition+ com,ared to the &''! u,dateof the third edition")

Table B ,ey cHAngeS Since THe THird ediTion

Cha*ter 1. IntroduCtIon

Xe sco,e is no limiXed Xo XreaXmenX of T% in adulXs" e fourXh ediXion no longerco9ers: T% case detection and diagnosis<

diagnosis and treatment of T% in children 5WHO has ,ublished a se,arateguideline on management of childhood T%8< drug su,,ly management"

X0nstead of Diagnostic categories 00Q+ this edition uses the same ,atient regis-tration grou,s used for recording and re,orting+ hich dierentiate ne ,atients

from those ith ,rior treatment and s,ecify reasons for retreatment"

Xach a,,licable sXandard from Xhe 0nXernaXional 2Xandards for T% Care is cross-referenced"

X*n eA,iry daXe is ,ro9ided"

Cha*ter 2. Case de!InItIons

Xe recenX WHO case deniXion for s,uXum smear-,osiXi9e ,ulmonary T%has&

been a,,lied to a de6nite case of T%+ so that no a ,atient ithone,ositi9e *F%smear is considered a de6nite case in countries ith a functional eAternal @ualityassurance 5I*8 system" 50n the third edition+ to ,ositi9e smears ere re@uired

before a ,atient could be considered a de6nite case"8

X%acXeriology no includes culXure and ne meXhods for idenXicaXion of $" tuber-culosis"

X.e WHO daXa elemenXs for recording and re,orXing+ such as H0 sXaXus and$D?-T%+ are included"

X2e9eriXy of disease is no longer included as a feaXure of Xhe case deniXion"

X0n Xhe deniXion for smear-negaXi9e T%+ Xhis ediXion incor,oraXes WHO ,olicyreducing the number of s,ecimens from three to to for screening ,atients sus-,ected to ha9e T%" This ,olicy a,,lies only in settings here a ell-functioning

I* system eAists+ the or=load is 9ery high+ and human resources are limited"

) htt,:##"ho"int#tb#,ublications#cdsYtbY&''Y)#en#indeA"html& htt,:##"ho"int#tb#dots#laboratory#,olicy#en#indeA)"html htt,:##"ho"int#tb#dots#laboratory#,olicy#en#indeA&"html

ExECuI(ESummary



1-


X0n seXXings iXh an H0 ,re9alence Z)V in ,regnanX omen or V in T% ,aXienXs+s,utum culture for$ycobacterium tuberculosisshould be ,erformed in ,atientsho are s,utum smear-negati9e to con6rm the diagnosis of T%"

X* Xrial of broad-s,ecXrum anXibioXics is no longer recommended Xo be used as adiagnostic aid for smear-negati9e ,ulmonary T% in ,ersons li9ing ith H0"

XFor H0-negaXi9e ,aXienXs+ Xhe fourXh ediXion s,ecies XhaX+ if broad-s,ecXrumantibiotics are used in the diagnosis of smear-negati9e ,ulmonary T%+ anti-T%

drugs and [uoro@uinolones should be a9oided"

XPulmonary T% cases iXhouX smear resulXs are no longer classied as smear-negati9e" 0nstead+ they are labelled smear not doneQ on the T% register and in the

annual WHO sur9ey of countries"

XConsisXenX iXh 2Xandard of Xhe 0nXernaXional 2Xandards for T% Care+ culXure andhisto,athological eAamination are recommended for s,ecimens from sus,ected

eAtra,ulmonary sites of T%" Aamination of s,utum and a chest radiogra,h arealso suggested+ in case ,atients ha9e concomitant ,ulmonary in9ol9ement"

Xe ,atient registration grou, OtherQ no longer includes chronicQ" 0nstead+,atients hose s,utum is smear-,ositi9e at the end of 5or returning from8 a sec-

ond or subse@uent course of treatment are classi6ed by the outcome of their mostrecent retreatment course: rela,sed+ defaulted or failed"

Cha*ter 3. standard treatment regImens

X*ddiXional dosage informaXion is ,ro9ided for isonia1id 5maAimum daily dose forthree times ,er ee=8 and stre,tomycin 5maAimum dose+ and adEustments in ,er-sons aged o9er 7' years or eighing less than /' =g8" Thioaceta1one is no longer

included among the 6rst-line drugs"

X* ne secXion on T% ,aXienX =iXs has been added"

Xe recommended ne ,aXienX regimen conXains 7 monXhs of rifam,icin< Xhe

regimen ith & months of rifam,icin 5ith the 7-month continuation ,hase of isonia1id and ethambutol8 is no longer an o,tion"

X0n Xhis ediXion+ Xhree Ximes ee=ly dosing XhroughouX Xhera,y is an alXernaXi9e onlyfor ,atients ho are recei9ing directly obser9ed thera,y of e9ery dose and ho are

not H0-,ositi9e or li9ing in an H0-,re9alent setting" Three times ee=ly dosingduring the intensi9e ,hase is no longer an o,tion for H0-,ositi9e T% ,atients or

T% ,atients li9ing in H0-,re9alent settings"

XWHO no recommends againsX Xice ee=ly dosing for Xhe full course of XreaX-

ment for ne ,atients 5unless done in the conteAt of formal research8"The thirdedition included the o,tion to omit ethambutol during the intensi9e ,hase of

treatment for ,atients ith non-ca9itary+ smear-negati9e ,ulmonary T% or eAtra-



11

,ulmonary disease ho are =non to be H0-negati9e" 0n the fourth edition+ theomission of ethambutol is no longer recommended"

Xis fourXh ediXion includes an alXernaXi9e conXinuaXion ,hase of eXhambuXol+

rifam,icin+ and isonia1id for ne ,atients in ,o,ulations ith high le9els of isoni-a1id resistance" This conditional recommendation a,,lies here isonia1id susce,-tibility testing in ne ,atients is not done 5or results are not a9ailable8 before the

continuation ,hase begins"

XD2T before or aX Xhe sXarX of Xhera,y is sXrongly recommended for all ,re9iouslytreated ,atients"

XPre9iously XreaXed ,aXienXs are dened by Xheir li=elihood of $D?-T%+ and rec-ommendations for treatment regimen de,end on reason for retreatment 5failure+

9ersus rela,se and default8"

XLaboraXory XesXs 5li@uid media+ line ,robe assays8 Xo meeX Xhe needs for Xhe ,rom,Xidenti6cation of $" tuberculosisand D2T are discussed+ based on country-s,eci6c+com,rehensi9e ,lans for laboratory strengthening"

XGuidance for sXarXing Xhera,y is ,ro9ided for ,re9iously XreaXed ,aXienXs+ basedon hether the country has access to ne ra,id molecular-based tests+ access to

con9entional D2T+ or no routine access to D2T results to guide management of indi9idual ,atients"

X0n counXries using con9enXional D2T+ a sXandard em,irical $D? regimen is rec-ommended for ,atients ith high li=elihood of $D?+ hile aaiting D2T results"

When D2T results become a9ailable+ regimens should be adEusted a,,ro,riately"

X*n $D? regimen is no recommended as one of each countryBs standard regi-mens+ for use in con6rmed $D?-T% cases as ell as in ,atients ith a high li=eli-hood of $D? hile aaiting D2T results" This edition also gi9es interim guidance

to countries here D2T is not yet routinely a9ailable for indi9idual retreatment,atients"

XGi9en Xhe a9ailabiliXy of funding from inXernaXional nancial mechanisms+ lac= of resources for $D? treatment is no longer an acce,table rationale for ,ro9iding a

retreatment regimen of 6rst-line drugs 5formerly called the Category & regimenQ8to ,atients ith a high li=elihood of $D?"

Xe ,re9ious ediXion recommended Xhe 4-monXh reXreaXmenX regimen iXh rsX-line drugs for all T% ,atients returning after defaulting or rela,sing" %y contrast+this edition allos for the ,ossibility that+ in some countries+ these ,atients may

ha9e le9els of $D?-T% that are high enough to arrant an $D? regimen hileaaiting results of D2T"

XWHO does noX inXend Xo esXablish Xhresholds for lo+ moderaXe+ or high li=eli-hoods or le9els of $D?" .TPs ill de6ne lo+Q moderateQ and highQ for their

ExECuI(ESummary



12


on countries+ based on le9els of $D? in s,eci6c ,atient grou,s+ as ell as otherfactors such as $D? treatment resources a9ailable during scale-u,+ and fre@uencyof concomitant conditions 5such as H08 that increase the short-term ris= of dying

from $D?-T%"

XCounXry drug resisXance sur9eys+ WHO esXimaXes of $D? le9els+ and oXher daXasources are recommended to inform decisions on each countryBs standard treat-

ment regimens for de6ned ,atient grou,s"

X0nXermiXXenX dosing is no longer an o,Xion for ,re9iously XreaXed ,aXienXs recei9ingthe 4-month retreatment regimen ith 6rst-line drugs"

Cha*ter %. monItorIng durIng treatment

Xe ,erformance of s,uXum smear microsco,y aX Xhe com,leXion of Xhe inXen-si9e ,hase of treatment is a conditional+ rather than a strong+ recommendation+

gi9en the e9idence that a ,ositi9e smear at this stage has a 9ery ,oor ability to ,re-dict rela,se or ,retreatment isonia1id resistance 5*nneA &8" Hoe9er+ its utility indetecting ,roblems ith ,atient su,er9ision and for monitoring ,rogramme ,er-

formance is reaSrmed"

X0n addiXion+ Xhis ediXion recommends XhaX a ,osiXi9e s,uXum smear aX Xhe end of the intensi9e ,hase in ne ,atients should trigger s,utum smear microsco,y atthe end of the third month" 0f the latter is ,ositi9e+ culture and D2T should be

,erformed"Xis ediXion no longer recommends eAXension of Xhe inXensi9e ,hase for ,aXienXsho ha9e a ,ositi9e s,utum smear at the end of the second month of treatment"

X0n ,re9iously XreaXed ,aXienXs+ if Xhe s,ecimen obXained aX Xhe end of Xhe inXensi9e,hase 5month 8 is smear-,ositi9e+ this edition recommends that s,utum culture

and D2T be ,erformed then+ rather than aiting until month / 5hich as recom-mended in the third edition8"

Xe ouXcome of cure no encom,asses culXure resulXs"XPaXienXs found Xo harbour an $D?-T% sXrain aX any ,oinX during XreaXmenX are

no classi6ed as treatment failureQ" They are re-registered and begin an $D?regimen"

XFor $D?-T% ,aXienXs+ Xhis ediXion recommends Xhe use of Xhe $D?-T% regisXerand cohort analysis"

Xe sym,Xom-based a,,roach Xo side-eecXs of anXi-T% drugs has been re9ised"



13

Cha*ter 5. Co&management o! hI( and aCtI(e t dIsease

XPro9ider-iniXiaXed H0 XesXing for all ,aXienXs iXh =non or sus,ecXed T% is norecommended+ regardless of the stage of the countryBs H0 e,idemic"

Xis ediXion includes currenX WHO recommendaXions Xo sXarX co-XrimoAa1ole assoon as ,ossible hen a ,erson li9ing ith H0 is diagnosed ith T%"

XDaily dosing is sXrongly recommended during Xhe inXensi9e ,hase for T% ,aXienXsith =non ,ositi9e H0 status+ and all ne ,atients li9ing in H0-,re9alentsettings" Three times ,er ee= dosing during the intensi9e ,hase is no longer an

acce,table alternati9e"

XCurrenX WHO recommendaXions for anXireXro9iral Xhera,y and Ximing of iniXia-tion are incor,orated"

XDrug susce,XibiliXy XesXing is no recommended aX Xhe sXarX of T% Xhera,y in all,eo,le li9ing ith H0"

Cha*ter ). su*er(IsIon and *atIent su**ort

X?oles of Xhe ,aXienX+ T% ,rogramme sXa+ Xhe communiXy+ and oXher ,ro9idersare described in assuring adherence to treatment" * treatment su,,orter must be

identi6ed for each T% ,atient+ hich may be a health or=er+ or a trained andsu,er9ised member of the community or family"

X TreaXmenX su,er9ision is dened in Xhe conXeAX of a larger su,,orX ,ac=age Xoaddress ,atientsB needs"

Cha*ter +. treatment o! drug&resIstant t

Xis cha,Xer has been eAXensi9ely re9ised Xo reecX recenX WHO recommendaXionsfor the ,rogrammatic management of drug-resistant T%"

Cha*ter ,. t treatment o! extra*u#monary dIsease and o! t In

s*eCIa# sItuatIons

XWhile WHO conXinues Xo recommend Xhe same regimens for eAXra,ulmonaryand ,ulmonary disease+ this fourth edition references other guidelines suggestinglonger treatment for T% meningitis and for bone or Eoint T%"

XFor T% ,aXienXs iXh ,re-eAisXing li9er disease+ Xhis fourXh ediXion includes regi-mens ith one+ to and no he,atotoAic drugs" * (-month regimen of rifam,icin

and ethambutol is no longer included as an o,tion"

XFor T% ,aXienXs iXh renal failure+ Xhis ediXion recommends Xhe 7-monXh regimenith isonia1id+ rifam,icin+ ethambutol and ,yra1inamide+ hereas the ,rior edi-

tion omitted ,yra1inamide" This edition recommends administering ethambutol5)/ mg#=g8 and ,yra1inamide 5&/ mg#=g8 three times ,er ee=" This edition nodiscourages the use of stre,tomycin in ,atients ith renal failure< hoe9er+ if itmust be used+ )/ mg#=g should be administered to to three times ,er ee=+ ith

monitoring of drug le9els"

ExECuI(ESummary



1%


annexes

annex 1

X?ifam,icin: includes a lisX of drugs hich inXeracX iXh rifam,icin"

X2Xre,Xomycin: dosage adEusXmenXs for Xhe elderly and adulXs eighing less Xhan/'=g are ,ro9ided"

XXhambuXol: creaXinine clearance \/' ml#min is no longer lisXed as a conXraindica-tion" Dosage adEustment in renal failure is ,ro9ided"

annex 2

Xis ne anneA describes Xhe e9idence base and issues XhaX ere considered in

ma=ing recommendations"

annex 3

Xis anneA describes Xhe mosX criXical XreaXmenX ouXcomes considered"

annex %

X0n Xhis ne anneA+ sXe,s for im,lemenXing and e9aluaXing Xhe sXrong recommen-dations are described"

annex 5Xis anneA ,ro9ides suggesXions for fuXure research under each of Xhe se9en @ues-

tions"

annex )

Xis ne anneA lisXs Xhe members of Xhe Guidelines Grou, and Xhe AXernal?e9ie Grou,"



15

1

introduction

1.1 Cha*ter o"4ectives

This cha,ter de6nes the ,ur,ose+ target audience+ sco,e and de9elo,ment of thisfourth edition of the guidelines" 0t also eA,lains hy a ne edition as needed and

,roEects a date for the neAt re9ision"

1.2 ur*ose o! the guide#ines The ,rinci,al ,ur,ose of these guidelines is to hel, national T% control ,rogrammes5.TPs8 in setting T% treatment ,olicy to o,timi1e ,atient cure: curing ,atients ill

,re9ent death+ rela,se+ ac@uired drug resistance+ and the s,read of T% in the commu-nity" Their further ,ur,ose is to guide clinicians or=ing in both ,ublic and ,ri9ate

sectors"

1.3 arget audience

The ,rimary target audience for the guidelines is the managers and sta of .TPs+together ith other T% ser9ice ,ro9iders or=ing in ,ublic and ,ri9ate health care

facilities at the central and ,eri,heral le9els"

Mse of the term .TP managerQ in these guidelines refers to the oScial ithin+ ordesignated by+ the ministry of health ho is res,onsible for the T% ,rogramme or to

that oScialBs designee"

1. % Sco*e

These guidelines address the treatment of acti9e T% disease in adults" They eAcludemany related to,ics that ha9e already been co9ered in detail in other ,ublications:diagnosis+ laboratory standards for smear microsco,y+ ,rotocols for use of ra,id drug

susce,tibility tests+ ,aediatric T%+ drug ,rocurement and su,,ly management+ in-fection control+ intensi6ed case-6nding in ,ersons li9ing ith H0+ and isonia1id

,re9enti9e thera,y"

1.5 hy a ne/ edition6

$aEor ,rogress in global T% control folloed the ides,read im,lementation of the

DOT2 strategy" The 2to, T% 2trategy+ launched in &''7+ builds u,on and enhancesthe achie9ements of DOT2 5)8: ne obEecti9es include uni9ersal access to ,atient-

centred treatment+ and ,rotection of ,o,ulations from T%#H0 coinfection andmultidrug-resistant T% 5$D?-T%8" The 2to, T% 2trategy and the Global Plan 5&8 to



1)


im,lement the ne strategy made it necessary to re9ise the eAisting guidelines 58and de9elo, this fourth edition"

Historically+ the greatest em,hasis of T% control acti9ities has been on the most in-

fectious ,atients those ho ha9e s,utum smear-,ositi9e ,ulmonary tuberculosis58" This changed ith the 2to, T% 2trategyBs em,hasis on uni9ersal access for all,ersons ith T% to high-@uality+ ,atient-centred treatment 5)8" Hoe9er+ highly in-

fectious+ smear-,ositi9e ,atients remain the ,rimary focus for other as,ects of T%control+ including contact tracing and infection control" The PatientsB Charter for T%

Care s,eci6es that all T% ,atients ha9e the right to free and e@uitable access to T%care+ from diagnosis through treatment com,letionQ 5!8"

This fourth edition of the guidelines has therefore abandoned Categories 00+ hich

ere used to ,rioriti1e ,atients for treatment" *ccording to this ,rior categori1ation+)

smear-negati9e T% ,atients ere assigned third ,riority and $D?-T% ,atients fourth,riority" For treatment decisions it no longer ma=es sense to assign third ,riorityto smear-negati9e ,atients gi9en their high mortality if they are li9ing ith H0"

@ually+ $D?-T% ,atients should not be assigned fourth ,riority+ gi9en their highmortality and the urgent need to ,re9ent the s,read of these deadliest T% strains"

To re,lace Categories 00+ this fourth edition grou,s ,atients 5and standard regi-mens recommended for each grou,8 according to the li=elihood of their ha9ing

drug resistance" Drug resistance is a critical determinant of treatment success+ and,rior T% treatment confers an increased ris= 5/+78"This edition uses the same ,atient

registration grou,s as those used for recording and re,orting+ hich dierentiatene ,atients from those ho ha9e had ,rior treatment 538" ?egistration grou,s for

,re9iously treated ,atients are based on the outcome of their ,rior treatment course:failure+ rela,se+ and default"

The fourth edition integrates detection and treatment of both H0 infection and$D?-T%+ and thus should contribute toards achie9ement of the 2to, T% 2trategyBs

uni9ersal access to high-@uality $D?-T% and H0 care"

With regard to H0 detection+ this edition incor,orates recent WHO recommenda-tions for ,ro9ider-initiated H0 testing of all ,ersons ith diagnosed or sus,ected

T%+ in all ty,es of H0 e,idemics 5lo-le9el+ concentrated or generali1ed8 548" Fortreatment of T% in ,ersons li9ing ith H0+ ne recommendations on the dura-

tion of thera,y and the role of intermittent regimens ha9e emerged from systematicre9ies 5see Cha,ter /8" The ne edition also includes recent WHO recommenda-

tions for D2T at the start of T% thera,y in all ,eo,le li9ing ith H0 5(8+ as ell asrecommendations on the timing and ty,e of antiretro9iral thera,y 5*?T8 regimens

5)'8")*lso+ the original one-to-one corres,ondence beteen ,atient grou, and treatment regimens as lost

as Categories 00 ere rede6ned o9er the years" The same treatment regimen came to be recommend-ed for ,atients in Categories 0 and 000< after &''!+ dierent treatment regimens ere recommended for

,atients in Category 00 de,ending on factors such as ,rogramme ,erformance and drug resistance"



1+

.e de9elo,ments in $D?-T% also contributed to the need for this re9ision" %uild-ing on the ,rinci,le of uni9ersal access to $D?-T% diagnosis and care+ The $D?-T%and JD?-T% res,onse ,lan &''3&''45))8 calls for the diagnosis and treatment of

$D?-T% in all countries by &')/" 9en countries ith lo o9erall le9els of multidrugresistance 5$D?8 are faced ith T% ,atients ho ha9e been ,re9iously treated agrou, that is 69e times more li=ely to ha9e $D?-T% than ne ,atients 5see section

"78"

0n terms of ensuring uni9ersal access to $D?-T% diagnosis+ this fourth edition reaf-6rms eAisting WHO recommendations 5&8 that all ,re9iously treated ,atients should

ha9e access to culture and D2T at the beginning of treatment+ in order to identify$D?-T% as early as ,ossible" 0t also incor,orates the WHO recommendation that)

treatment failure be con6rmed by culture and D2T 5(8"0n order to detect $D? soon-

er than the end of the 6fth month of treatment+ this edition includes the eAistingWHO recommendation 5(8 for culture and D2T if ,atients still ha9e smear-,ositi9es,utum at the end of the third month of treatment"

Cha,ters &] of this ne edition discuss the critical role of the identi6cation of $yco-bacterium tuberculosisand of D2T" This is in contrast to the ,re9ious edition+ hich

relied almost eAclusi9ely on smear microsco,y for case de6nition+ assignment of stand-ard regimens+ and monitoring of treatment res,onse" Line ,robe assays can identify

$D?-T% ithin hours and li@uid media can do so ithin ee=s 5rather than months

hen solid media are used8 5)&8" These techni@ues should be introduced in line ithcom,rehensi9e+ country-s,eci6c ,lans for laboratory ca,acity strengthening"

To mo9e toards uni9ersal access to $D?-T% treatment+ the fourth edition includesa ne recommendation for e9ery country to include an $D? regimen in its stand-

ard regimens" This is essential hile aaiting D2T results for ,atients ith a highli=elihood of $D? 5such as those hose ,rior treatment ith a 7-month rifam,icin

regimen has failed8+ and for ,atients in hom resistance to isonia1id and rifam,icin iscon6rmed" With the a9ailability of funding from international 6nancial ,artners+ lac=&

of resources for $D?-T% treatment is no longer an acce,table rationale for ,ro9idingthe 4-month retreatment regimen ith 6rst-line drugs 5formerly called the Category00 regimenQ8 to ,atients ith a high li=elihood of $D?< this regimen is ineecti9e in

treating $D?-T% and may result in am,li6cation of drug resistance 5/+)8"

Mse of ra,id D2T methods ill e9entually render the 4-month retreatment regimenof 6rst-line drugs obsolete" 0n the meantime+ the regimen is retained in this fourth

edition in only to circumstances" 0n countries ith access to routine D2T usingcon9entional methods+ the 4-month retreatment regimen ith 6rst-line drugs is

recommended hile aaiting D2T results from ,atients ho ha9e rela,sed or arereturning after default 5if country-s,eci6c data sho they ha9e a medium li=elihood

) This recommendation is consistent ith the 0nternational 2tandards for Tuberculosis Care and resolu-tions endorsed by the World Health *ssembly in &''3 hich call for uni9ersal access to D2T by &')/"

& 2uch as M.0T*0D and the Global Fund to Fight *0D2+ Tuberculosis and $alaria"

1. I nroduCIon



1,


of $D?-T%+ or if such data are una9ailable8" 0n countries that do not yet ha9e D2Troutinely a9ailable at the start of treatment for all ,re9iously treated ,atients 5see sec-

tion "3"8+ the 4-month retreatment regimen ith 6rst-line drugs ill be used for theduration of treatment on an interim basis until laboratory ca,acity is a9ailable"

0n ,rinci,le+ $D? treatment should be introduced only in ell-,erforming DOT2,rogrammes" %efore focusing on curing $D?-T% cases+ it is critical to turn o theta,Q+ i"e" to strengthen ,oor ,rogrammes so that they sto, gi9ing rise to $D?-T%"

Folloing this ,rinci,le+ the &''! re9ision of the treatment cha,ter listed ade@uate)

,erformance of a countryBs o9erall T% ,rogramme as a re@uirement for the use of $D? regimens in ,atients ith a high li=elihood of $D?" This is no longer a ,re-

re@uisite in the fourth edition" 0n some countries ith limited DOT2 co9erage+ theremay be an a,,ro,riate setting for an $D? ,ilot ,roEect that+ once established+ can

,ro9ide a model and an im,etus for the eA,ansion of basic DOT2 into more areas"0n most countries+ hoe9er+ conditions for initiating an $D? com,onent in most

.TPs are not met until the o9erall .TP has the essential elements of DOT2 6rmlyin ,lace"

1.) methodo#ogy

De9elo,ment of the fourth edition of the guidelines folloed ne WHO ,rocedures"WHO de6ned the sco,e of re9ision and con9ened a guidelines grou, of eAternal

eA,erts" *ll members of the grou, com,leted a Declaration for the Con[ict of 0nter-est< there ere no con[icts declared" With in,ut from the Guidelines Grou,+ WHOidenti6ed se9en =ey @uestions on the treatment of T% 5see *nneA &8 co9ering the

folloing to,ics:

duration of rifam,icin in ne ,atients< dosing fre@uency in ne ,atients<

initial regimen for ne T% ,atients in countries ith high le9els of isonia1idresistance<

T% treatment in ,ersons li9ing ith H0< s,utum monitoring during T% treatment< treatment eAtension< retreatment"

2ystematic literature re9ies ere conducted for each @uestion and the e9idence assynthesi1ed 5see *nneA &8"&

0n,ut from the Guidelines Grou, to the re9ision of guidelines as made by e-mail+ inconference calls and at a -day meeting 5&)& October &''48 during hich the 6nal

treatment recommendations ere established once consensus had been reached by) Treatment of tuberculosis: guidelines for national ,rogrammes+ rd ed" Cha,ter !+ 2tandard treatment

regimens+ as re9ised in une &''! and the ne 9ersion as ,osted on the WHO eb site"&*t the time of ,ublication of this fourth edition+ e9idence gathered through some of the systematic

re9ies had not been ,ublished"



19

the Guidelines Grou," The recommendations are based on the @uality of the e9idence+9alues+ and costs+ as ell as Eudgements about trade-os beteen bene6ts and harm"

The grou, graded the strength of each recommendation+ re[ecting the degree of con-

6dence that the desirable eects of adherence to a recommendation outeigh theundesirable eects" *lthough the degree of con6dence is necessarily a continuum+

three categories are used strong+ conditional and ea=" The @uality of the e9idenceas assessed according to the G?*D methodology 5)!8"

$oderate#lo @uality of e9idence means that the estimate of eect of the inter9en-tion is 9ery uncertain and further research is li=ely to ha9e an im,ortant im,act oncon6dence in the estimate" For high-@uality e9idence+ by contrast+ further research

is unli=ely to change con6dence in the estimate of eect"

* strong recommendation means that the desirable eects of adherence to the rec-ommendation clearly outeigh the undesirable eects" 2trong recommendations use

the ords shouldQ or should notQ" .o alternati9es are listed"

* conditional recommendation means that the desirable eects of adherence to therecommendation ,robably outeigh the undesirable eects+ but the trade-os are

uncertain" ?easons for lac= of certainty include:

high-@uality e9idence to su,,ort the recommendation is lac=ing< bene6ts of im,lementing the recommendation are small<

bene6ts may not Eustify the costs< it as not ,ossible to arri9e at ,recise estimates of bene6t"

* ea= recommendation means that there is insuScient e9idence< the recommenda-tion is therefore based on 6eld a,,lication and eA,ert o,inion"

Conditional and ea= recommendations use the ord mayQ" *lternati9es are listedfor se9eral of the conditional recommendations"

Table )") shos ho strong and conditional recommendations dier in terms both

of ording and of the factors used to Eudge their strength" 2trong and conditionalrecommendations also ha9e dierent im,lications for ,olicy-ma=ers+ ,atients+ and

health care ,ro9iders< these are summari1ed in the table"

* ,lan for im,lementing and e9aluating the strong recommendations is outlined in*nneA !" To address the ga,s in the e9idence critical for decision-ma=ing+ the Guide-lines Grou, de9elo,ed a series of @uestions as a basis for future research< these are

detailed in *nneA /" $embers of the Guidelines Grou, are listed in *nneA 7"

The recommendations that address the se9en =ey @uestions a,,ear in the conteAt

of guidance on standard treatment 5Cha,ter 8+ monitoring 5Cha,ter !8 and H05Cha,ter /8" *reas outside the sco,e of those @uestions ha9e been u,dated ith cur-rent references and WHO T% ,olicies but ere not the subEect of systematic literature

re9ies or of ne recommendations by the Guidelines Grou,"

1. I nroduCIon



2-


Table -(- STrong 'erSuS condiTionAl recommendATionS

recommendation strength

Strong Conditiona#

hrasing o! therecommendation

.Shou#d/ or .shou#d not/(

no alternatives are presented

.7*tima# is/! .may/! or .it

is 8not recommended/(

Alternatives are often listed

!actors used to 4udge strength

quality of evidence High$quality evidence low$quality evidence

Balance between

desirable and undesirable

effects on patient and

public health

large! certain net bene0t and1or

difference between bene0ts and

harms or burdens

Small and1or uncertain

gradient

resource allocation low cost "or little uncertainty

about whether the intervention

represents a wise use of

resources#

High cost "or high

uncertainty#

uncertainty in values and

preferences variability

across patients

Small amount of uncertainty or

variability

large amount of uncertainty

or variability

Im*#ications

!or *o#icy&maers

"including nTp

managers#

The recommendation should

unequivocally be used for

setting policy

policy$ma&ing will require

e%tensive debate

!or *atients most individuals would want the

recommended course of action

The recommended course

of action can be ad3usted on

the basis of feasibility and

acceptability!or hea#th care

*roviders

most patients should be treated

according to the recommended

course of action( Adherence

to this recommendation is a

reasonable measure of good

quality care



21

The draft guidelines ere circulated to the eAternal re9ie grou, 5hose membersare listed in *nneA 78+ made u, of .TP managers from high-burden countries+ mem-

bers of the WHO 2trategic+ Technical and *d9isory Grou, on T% 52T*G-T%8+ siAregional T% *d9isers and T% medical oScers or=ing in high-burden countries"

Comments recei9ed from the eAternal re9ie grou, ere a,,ro,riately addressedand the fe disagreements beteen the eAternal re9ieers and the Guidelines Grou,

ere resol9ed by e-mail consultation"

1.+ Internationa# Standards !or u"ercu#osis Care

The0nternational 2tandards for Tuberculosis Care502TC8 5)/8 describe a idely ac-ce,ted le9el of T% care that all ,ractitioners should see= to achie9e" Cross-referencing

the a,,licable 02TC standards in this ne edition should hel, ,ro9iders in both ,ub-lic and ,ri9ate sectors to ensure their im,lementation"

1., Ex*iry date

The WHO 2to, T% De,artment ill re9ie and u,date these guidelines after /years or as needed hen ne e9idence+ treatment regimens or diagnostic tests

become a9ailable"

re!erences?a9iglione $C+ M,le=ar $W" WHOBs ne sto, T% strategy")" Lancet+&''7+ 73:(/&(//" The global ,lan to sto, T%+ &''7&')/&" " Gene9a+ World Health Organi1ation+ &''75WHO#HT$#2T%#&''7"/8" Treatment of tuberculosis: guidelines for national ,rogrammes" + rd ed" Gene9a+ WorldHealth Organi1ation+ &'' 5WHO#CD2#T%#&''")8"PatientsB charter for tuberculosis care: ,atientsB rights and res,onsibilities!" " Gene9a+

World Care Council+ &''7 5a9ailable at: "ho"int#tb#,ublications#&''7#,atientsY charter",df8"

s,inal $* et al" 2tandard short-course chemothera,y for drug-resistant tuberculo-/"sis: treatment outcomes in 7 countries" ournal of the *merican $edical *ssociation+&'''+ &4:&/3&/!/"

*1i1 $* et al" ,idemiology of antituberculosis drug resistance 5the Global ProEect7"on *nti-tuberculosis Drug ?esistance 2ur9eillance8: an u,dated analysis"Lancet+&''7+ 74:&)!&&)/!"?e9ised T% recording and re,orting forms and registers 9ersion &''73" "Gene9a+ World

Health Organi1ation+ &''7 5WHO#HT$#T%#&''7"3< a9ailable at: "ho"int#tb#dots#rYandYrYforms#en#indeA"html8"

Guidance on ,ro9ider-initiated H0 testing and counselling in health facilities4" "Gene9a+ World Health Organi1ation+ &''3"Guidelines for the ,rogrammatic management of drug-resistant tuberculosis: emer-("

gency u,date &''4" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$#T%#&''4"!'&8"

1. I nroduCIon



22


*ntiretro9iral thera,y for H0 infection in adults and adolescents in resource-limited)'"settings: recommendations for a ,ublic health a,,roach" Gene9a+ World Health Or-gani1ation+ &''7" The global $D?-T% ^ JD?-T% res,onse ,lan &''3&''4))" "Gene9a+ World Health Or-

gani1ation+ &''3 5WHO#HT$#T%#&''3"438"$olecular line ,robe assays for ra,id screening of ,atients at ris= of $D? T%: ,olicy)&"

statement"Gene9a+ World Health Organi1ation+ &''4 5a9ailable at: "ho"int#tb#featuresYarchi9e#,olicyYstatement",df8"

s,inal $*" Time to abandon the standard retreatment regimen ith 6rst-line)"drugs for failures of standard treatment"0nternational ournal of Tuberculosis andLung Disease+ &''+ 3:7'37'4"

Guyatt GH et al" G?*D: an emerging consensus on rating @uality of e9idence and)!"strength of recommendations"%ritish $edical ournal+ &''4+ 7:(&!(&7"

0nternational 2tandards for Tuberculosis Care 502TC8)/" + &nd ed" The Hague+ Tuberculo-sis Coalition for Technical *ssistance+ &''("



23

2

Case de6nitions


This cha,ter describes

the ,ur,ose of ha9ing case de6nitions for tuberculosis< the de6nition of a case of T%+ as ell as of sus,ected and con6rmed cases<

additional features of T% cases im,ortant for the treatment of indi9idual ,a-

tients+ as ell as for e9aluating T% ,rogrammes and monitoring the e,idemic" The diagnosis of T% refers to the recognition by health or=ers 5medical oScer+

nurse+ ,aramedic or other8 of an acti9e case+ i"e" a ,atient ith current disease due to$" tuberculosis" The role of .TPs is dierent: they are res,onsible for ensuring thatdiagnosed cases are noti6ed 5)8+ meet the de6nition for case or de6nite case+ and aretreated a,,ro,riately+ and that outcomes are e9aluated")

*ll ,ro9iders must re,ort both ne and retreatment T% cases and their treatmentoutcomes to local ,ublic health authorities+ in conformance ith a,,licable legal re-

@uirements 52tandard &) of the 02TC 5/88".TPs ensure that critical features of the T%case are recorded and re,orted so that treatment is a,,ro,riate and feedbac= is ,ro-9ided to the treating clinician 578"*nalysis of these re,orts also hel,s the .TP man-

ager to monitor trends and e9aluate the eecti9eness of T% acti9ities at all le9els"

2.2 ur*oses o! defining a " case

Mniform criteria to de6ne a T% case are needed for:

,ro,er ,atient registration and case noti6cation<

selecting a,,ro,riate standard treatment regimens 5see Cha,ter 8< standardi1ing the ,rocess of data collection for T% control< e9aluating the ,ro,ortion of cases according to site+ bacteriology and treat-

ment history< cohort analysis of treatment outcomes<

accurate monitoring of trends and e9aluation of the eecti9eness of T% ,ro-grammes ithin and across districts+ countries and global regions"

2.3 Case definitions

The T% case de6nitions belo are based on the le9el of certainty of the diagnosis andon hether or not laboratory con6rmation is a9ailable"

).TP ,rogrammes also facilitate the detection of cases 9ia s,utum screening of sus,ects ith coughattending health facilities 5&8+ as ell as screening of contacts 58 and screening of ,ersons li9ing ithH0#*0D2 5!8"



2%


X Tu)erculosis suspect" *ny ,erson ho ,resents ith sym,toms or signs sugges-ti9e of T%" The most common sym,tom of ,ulmonary T% is a ,roducti9e cough for

more than & ee=s+ hich may be accom,anied by other res,iratory sym,toms)

5shortness of breath+ chest ,ains+ haemo,tysis8 and#or constitutional sym,toms5loss of a,,etite+ eight loss+ fe9er+ night seats+ and fatigue8"&

X >ase o# tu)erculosis"* de6nite case of T% 5de6ned belo8 or one in hich ahealth or=er 5clinician or other medical ,ractitioner8 has diagnosed T% and has

decided to treat the ,atient ith a full course of T% treatment"

.ote"*ny ,erson gi9en treatment for T% should be recorded as a case" 0ncom,letetrialQ T% treatment should not be gi9en as a method for diagnosis"

X :e9nite case o# tu)erculosis"* ,atient ith$ycobacterium tuberculosiscom,leA

identi6ed from a clinical s,ecimen+ either by culture or by a neer method suchas molecular line ,robe assay" 0n countries that lac= the laboratory ca,acity to

routinely identify$" tuberculosis+ a ,ulmonary case ith one or more initial s,u-tum smear eAaminations ,ositi9e for acid-fast bacilli 5*F%8 is also considered to

be a de6niteQ case+ ,ro9ided that there is a functional eAternal @uality assurance5I*8 system ith blind rechec=ing"

Cases of T% are also classi6ed according to the:

anatomical site of disease<

bacteriological results 5including drug resistance8< history of ,re9ious treatment< H0 status of the ,atient"

ach of these =ey features of T% cases is discussed belo"

2.% anatomica# site o! " disease

0n general+ recommended treatment regimens are similar+ irres,ecti9e of site 5see sec-tion 4"&8" De6ning the site is im,ortant for recording and re,orting ,ur,oses and toidentify the more infectious ,atients those ith ,ulmonary in9ol9ement 5ho ill

be further subdi9ided by smear status see section &"/ belo8"

?ulmonary tu)erculosis5PT%8 refers to a case of T% 5de6ned abo9e8 in9ol9ing thelung ,arenchyma" $iliary tuberculosis is classi6ed as ,ulmonary T% because there

are lesions in the lungs" Tuberculous intrathoracic lym,hadeno,athy 5mediastinaland#or hilar8 or tuberculous ,leural eusion+ ithout radiogra,hic abnormalities in

the lungs+ constitutes a case of eAtra,ulmonary T%" * ,atient ith both ,ulmonaryand eAtra,ulmonary T% should be classi6ed as a case of ,ulmonary T%"

) 2tandard ) of the 0nternational 2tandards for T% Care 5/8 states that all ,ersons ith otherise uneA-,lained ,roducti9e cough lasting & ee=s or more should be e9aluated for T%"

& The de6nition of a T% sus,ectQ de,ends on other local factors+ including the ,atientBs age and H0status+ H0 ,re9alence in the ,o,ulation+ T% ,re9alence in the ,o,ulation+ etc"

2ee: "ho"int#tb#dots#laboratory#,olicy#en#indeA)"html"



25

2. C aSE dE!InIIonS

&6trapulmonary tu)erculosis5PT%8 refers to a case of T% 5de6ned abo9e8 in9ol9-ing organs other than the lungs+ e"g" ,leura+ lym,h nodes+ abdomen+ genitourinary

tract+ s=in+ Eoints and bones+ meninges" Diagnosis should be based on at leastone s,ecimen ith con6rmed$" tuberculosisor histological or strong clinical e9idence

consistent ith acti9e PT%+ folloed by a decision by a clinician to treat ith a fullcourse of tuberculosis chemothera,y" The case de6nition of an PT% case ith se9-

eral sites aected de,ends on the site re,resenting the most se9ere form of disease"Mnless a case of PT% is con6rmed by culture as caused by$" tuberculosis+ it cannotmeet the de6nite caseQ de6nition gi9en in section &" abo9e"

2.5 "acterio#ogica# resu#ts

%acteriology refers to the smear status of ,ulmonary cases and the identi6cation of

$" tuberculosisfor any case by culture or neer methods" Culture and drug susce,-tibility testing are discussed in section "4")" For de6nitions of $D?-T% cases+ see

reference3"

2tandard & of the 02TC 5/8states that all ,atients sus,ected of ha9ing ,ulmonary T%should submit at least to s,utum s,ecimens for microsco,ic eAamination in a @ual-

ity-assured laboratory" When ,ossible+ at least one early-morning s,ecimen shouldbe obtained+ as s,utum collected at this time has the highest yield" 02TC 2tandard !states that all ,ersons ith chest radiogra,hic 6ndings suggesti9e of T% should sub-

mit s,utum s,ecimens for microbiological eAamination 5/8"2mear-,ositi9e cases are the most infectious and most li=ely to transmit their dis-

ease in their surroundings< they are the focus for infection control measures 5&8andcontact in9estigations 58" %acteriological monitoring of treatment ,rogress is mostfeasible and ,racticable in these ,atients 5see Cha,ter !8"

0t is also im,ortant to identify smear-negati9e cases+ es,ecially in ,ersons li9ing ithH0 for hom mortality is higher than in smear-,ositi9e ,ulmonary T% cases 5!8"Fordiagnostic algorithms for smear-negati9e ,ersons li9ing ith H0+ see reference!"

* case of ,ulmonary T% is considered to besmear-,ositi9eif one or more s,utumsmear s,ecimens at the start of treatment are ,ositi9e for *F% 5,ro9ided that there is

a functional I* system ith blind rechec=ing 8")

The de6nition of a ne s,utum smear-,ositi9e ,ulmonary T% case is based on the,resence of at least one acid fast bacillus 5*F%;8 in at least one s,utum sam,lein countries ith a ell functioning I* system" 52ee "ho"int#tb#dots#laboratory#

,olicy#en#indeA)"html"8

)

0n countries ithout functional I*+ the de6nition from the third edition of these guidelines a,,lies:a smear-,ositi9e ,ulmonary T% case as de6ned as one ith:

a" to or more initial s,utum smear eAaminations ,ositi9e for *F%+orb" one s,utum smear eAamination ,ositi9e for *F% ,lus radiogra,hic abnormalities consistent ith

acti9e PT% as determined by a clinician+orc" one s,utum smear ,ositi9e for *F% ,lus s,utum culture-,ositi9e for$" tuberculosis"



2)


2mear-negati9ePT% cases should either:

*" ha9e s,utum that is smear-negati9e but culture-,ositi9e for$" tuberculosis:

Xa case of ,ulmonary T% is considered Xo besmear-negati9eif at least tos,utum s,ecimens at the start of treatment are negati9e for *F% in countries)

ith a functional I* system+ here the or=load is 9ery high and humanresources are limited 5see htt,:###"ho"int#tb#dots#laboratory#,olicy#en#

indeA&"html8<

Xin all seXXings iXh an H0 ,re9alence of Z)V in ,regnanX omen or V in T%,atients+ s,utum culture for$" tuberculosisshould be ,erformed in ,atientsho are s,utum smear-negati9e to con6rm the diagnosis of T% 5!8"

O?%" meet the folloing diagnostic criteria: 57_ 8

Xdecision by a clinician Xo XreaX iXh a full course of anXi-T% Xhera,y< and

Xradiogra,hic abnormaliXies consisXenX iXh acXi9e ,ulmonary T% and

either:

laboratory or strong clinical e9idence of H0 infection

or:

if H0-negati9e 5or un=non H0 status li9ing in an area of lo H0 ,re9a-lence8+ no im,ro9ement in res,onse to a course of broad-s,ectrum antibiot-

ics 5eAcluding anti-T% drugs and [uoro@uinolones and aminoglycosides8"

Pulmonary T% cases ithout smear results are no longer classi6ed as smear-negati9e5!8< instead+ they are recorded as smear not doneQ on the T% register 578 and on theannual WHO sur9ey of countries"

For ,atients sus,ected of ha9ing PT%+ s,ecimens should be obtained from the sus-,ected sites of in9ol9ement 52tandard of the 02TC 5/88" Where a9ailable+ culture

and histo,athological eAamination should also be carried out" *dditionally+ a chestJ-ray and eAamination of s,utum may be useful+ es,ecially in ,ersons ith H0

infection"

2. ) 'istory o! *revious treatment: *atient registration grou*

*t the time of registration+ each ,atient meeting the case de6nition is also classi6edaccording to hether or not he or she has ,re9iously recei9ed T% treatment and+ if so+the outcome 5if =non8" 0t is im,ortant to identify ,re9iously treated ,atients because

they are at increased ris= of drug resistance+ including $D?-T% 5see section "78"*t the start of thera,y+ s,ecimens should be obtained for culture and D2T from all,re9iously treated ,atients" Treatment de,ends on hether the ,atient has rela,sed

) *nd no s,ecimen is smear-,ositi9e"



2+

or is returning after default or after ,rior treatment has failed 5see section "38" Thedistinctions beteen ne and ,re9iously treated ,atients+ and among the subgrou,sof ,re9iously treated ,atients+ are also essential for monitoring the T% e,idemic and

,rogramme ,erformance"

New patientsha9e ne9er had treatment for T%+ or ha9e ta=en anti-T% drugs for lessthan ) month" .e ,atients may ha9e ,ositi9e or negati9e bacteriology and may ha9e

disease at any anatomical site"

?re!iously treated patientsha9e recei9ed ) month or more of anti-T% drugs in the,ast+ may ha9e ,ositi9e or negati9e bacteriology and may ha9e disease at anyana-tomical site" They are further classi6ed by the outcome of their most recent course of

treatment as shon in Table &") belo"

Patients hose s,utum is smear-,ositi9e at the end of 5or returning from8 a secondor subse@uent course of treatment are no longer de6ned as chronicQ" 0nstead+ they

should be classi6ed by the outcome of their most recent retreatment course: rela,sed+defaulted or failed"

2. C aSE dE!InIIonS

Table 2(- regiSTrATion group By ouTcome of moST recenT

TB TreATmenT

registration grou*"any site of disease#

"acterio#ogy a outcome o! most recent *rior treatment8defined in a"#e %.1

ne/ or 5 5

revious#y treated re#a*se cured

Treatment completed

!ai#ure Treatment failed

de!au#t defaulted

rans!er in+ A patient who has

been transferred from another TB

register to continue treatment

or 5 Still on treatment

other or 5 All cases that do not 0t the above

de0nitions! such as patients

6 for whom it i6 not &nown whether

they have been previously treated

6 who were previou6ly treated but with

un&nown outcome of that previous

treatment "3! 8# and1orb

6 who have returned to treatment

with smear$negative pTB or

bacteriologically negative epTB "3# b

a indicates positive smear! culture or other newer means of identifying M. tuberculosis

5 indicates that any specimens tested were negative(b de0ned as .other retreatment/ in other wHo documents cited above(



2,


2.+ 'I( status

Determining and recording the ,atientBs H0 status is critical for treatment decisions5see Cha,ters and /8 as ell as for monitoring trends and assessing ,rogramme

,erformance" WHOBs re9ised T% Treatment Card and T% ?egister include dates of H0 testing+ starting co-trimoAa1ole+ and starting *?T" These im,ortant inter9en-tions are discussed more fully in Cha,ter /"

re!erences

ngaging all health care ,ro9iders in T% control: guidance on im,lementing ,ublic-)",ri9ate miA a,,roaches" Gene9a+ World Health Organi1ation+ &''7 5WHO#HT$# T%#&''7"7'8"

WHO ,olicy on T% infection control in health care facilities+ congregate settings and&"

households" Gene9a+ World Health Organi1ation+ &''( 5WHO#HT$#T%#&''("!)(8"0m,lementing the WHO 2to, T% 2trategy: a handboo= for national tuberculosis control"

,rogrammes" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$#T%#&''4"!'8"0m,ro9ing the diagnosis and treatment of smear-negati9e ,ulmonary and eAtra,ulmo-!"nary tuberculosis among adults and adolescents: recommendations for H0-,re9alent

and resource-constrained settings"Gene9a+ World Health Organi1ation+ &''3 5WHO#HT$#T%#&''3"3(< WHO#H0#&''3")8"0nternational 2tandards for Tuberculosis Care 502TC8/" + &nd ed" The Hague+ Tuberculo-sis Coalition for Technical *ssistance+ &''("

?e9ised T% recording and re,orting forms and registers 9ersion &''77" "Gene9a+ WorldHealth Organi1ation+ &''7 5WHO#HT$#T%#&''7"3< a9ailable at: "ho"int#tb#dots#rYandYrYforms#en#indeA"html8"

Guidelines for the ,rogrammatic management of drug-resistant tuberculosis: emer-3"gency u,date &''4" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$#T%#&''4"!'&8"

Global tuberculosis control &''(: e,idemiology+ strategy+ 6nancing" WHO re,ort &''(4" "Gene9a+ World Health Organi1ation+ &''( 5WHO#HT$#T%#&''("!))8"



29

3

standard treatment regimens


This cha,ter describes:

the aims of treatment< the recommended doses of 6rst-line anti-T% drugs for adults< regimens for ne and ,re9iously treated ,atients<

considerations in selecting regimens for de6ned ,atient grou,s< e9idence base for the selected regimens in de6ned ,atient grou,s"

The choice of T% regimens in s,ecial situations 5,regnancy+ concurrent use of oralcontrace,ti9es+ li9er disease+ and renal failure8 is co9ered in Cha,ter 4< T% treatment

for ,ersons li9ing ith H0 is discussed in Cha,ter /"

3.2 aims o! treatment

The aims of treatment of tuberculosis are:

to cure the ,atient and restore @uality of life and ,roducti9ity< to ,re9ent death from acti9e T% or its late eects< to ,re9ent rela,se of T%< to reduce transmission of T% to others< to ,re9ent the de9elo,ment and transmission of drug resistance"

3.3 Essentia# antitu"ercu#osis drugs

Table ") shos the essential anti-T% drugs and their recommended dosages based

on the ,atientBs eight" The WHO-recommended formulations of anti-T% drugs and 6Aed-dose combina-

tions 5FDCs8 of drugs a,,ear in theWHO $odel List of ssential $edicines5a9ailableat "ho"int#medicines#,ublications#essentialmedicines#en8" The formulationsand combinations of anti-T% drugs a9ailable in each country should conform to this

list" 52ee also the WHO $odel Formulary at "ho"int#selectionYmedicines#list#en"8

To facilitate ,rocurement+ distribution and administration of treatment to ,atients+

the daily dosage may be standardi1ed for three or four body eight bands forinstance '( =g+ !'/! =g+ //3' =g and o9er 3' =g+ as is done ith theGlobalDrug Facility ,atient =its" 52ee also reference)"8



3-


*ll anti-T% drugs should be @uality-assured+ and management of anti-T% drugsshould be incor,orated into the management of other essential medicines by the

ministry of health"*nneA ) ,ro9ides additional information on the essential anti-T% drugs+ including

contraindications+ ,recautions+ use in ,regnancy+ ad9erse eects+ and drug inter-actions" 0ntermittent dosing schedules are discussed in section "/") belo"

)()(- fi%ed$dose combinations of anti$TB drugs

While e9idence on 6Aed-dose combinations 5FDCs8 of anti-T% drugs as not system-atically re9ieed for this fourth edition+ WHO continues to recommend their use+

as does 2tandard 4 of the 02TC 58" FDCs are thought to ,re9ent ac@uisition of drugresistance due to monothera,y+ hich may occur ith se,arate 5looseQ8 drugs" WithFDCs+ ,atients cannot be selecti9e in the choice of drugs to ingest" Prescri,tion errorsare li=ely to be less fre@uent because dosage recommendations are more straightfor-ard+ and adEustment of dosage according to ,atient eight is easier" The number of

tablets to ingest is smaller and may thus encourage ,atient adherence"

While there is ecological e9idence of the bene6ts of FDCs in relation to drug re-sistance in early studies of DOT2 ,rogrammes+ there is limited direct e9idence of

im,ro9ed adherence ith FDCs 5!8" * recent multicentre trial found FDCs to ha9ee@ui9alent eScacy to single ,ills and to be more acce,table to ,atients 5/8"Hoe9er+

assessment of cure and rela,ses as based on smear microsco,y and not on culture"* multicentre trial 5The Mnion 2tudy C8 e9aluating the eScacy+ acce,tability and

toAicity of a four-drug FDC com,ared ith loose ,ills gi9en in the intensi9e ,hase

Table )(- recommended doSeS of firST$line AnTiTuBerculoSiS drugS

for AdulTS

drug

recommended dose

dai#y 3 times *er /ee

dose and range"mg1&g body

weight#

maximum"mg#

dose and range"mg1&g body

weight#

dai#y maximum"mg#

isoniaid * "457# )88 -8 "95-2# :88

rifampicin -8 "95-2# 788 -8 "95-2# 788

pyrainamide 2* "285)8# 5 )* ")8548# 5

ethambutol -* "-*528# 5 )8 "2*5)*# 5

Streptomycina

-* "-25-9# -* "-25-9# -888

a patients aged over 78 years may not be able to tolerate more than *885;*8 mg daily! so some guide$

lines recommend reduction of the dose to -8 mg1&g per day in patients in this age group " 2#( patients

weighing less than *8 &g may not tolerate doses above *885;*8 mg daily "WHO Model Formulary 2008!

www(who(int1selection<medicines1list1en1#(



31

3. S andard rEamEn rE$ImEnS

of treatment has Eust been com,leted and results should soon be a9ailable" *nothermulticentre study including ,harmaco=inetic assessment is soon to be com,leted by

WHO#TD?"

Iuality assurance is essential to ensure ade@uate bioa9ailability of the com,o-nent drugs of FDCs" Msing FDCs does not ob9iate the need for se,arate drugs for)

,atients ho de9elo, drug toAicity or intolerance or for those ith contraindicationsto s,eci6c com,onent drugs"

)()(2 patient &its

* T% ,atient =it contains the full course of treatment for a single ,atient and thus as-sures the T% ,atient that his or her medicines ill be a9ailable throughout treatment"

The =it ,ro9ides health or=ers ith a container that has all re@uired medicines inthe necessary strengths and @uantities" This hel,s limit confusion and astage+ andma=es it easier to monitor the regularity of treatment< a9oiding stoc=-outs also hel,sto maintain ,atient con6dence in the health system" 0n addition+ the ,atient may feel

a sense of onershi,Q of the ,atient =it and enhanced moti9ation to com,lete thefull course of treatment during 9isits to the health centre he or she can actually see

the @uantity of medicines that must be ta=en to achie9e cure 5)8"

0t should be noted that the T% ,atient =it does not eliminate the need fordirectlyobser9ed treatment 5DOT8"

3. % Standard regimens !or defined *atient grou*s

2tandardi1ed treatment means that all ,atients in a de6ned grou, recei9e the sametreatment regimen" 2tandard regimens ha9e the folloing ad9antages o9er indi9idu-

ali1ed ,rescri,tion of drugs:

errors in ,rescri,tion and thus the ris= of de9elo,ment of drug resistance are reduced<

estimating drug needs+ ,urchasing+ distribution and monitoring are facilitat-ed<

sta training is facilitated< costs are reduced<

maintaining a regular drug su,,ly hen ,atients mo9e from one area to an-other is made easier<

outcome e9aluation is con9enient and results are com,arable"

For assigning standard regimens+ ,atients are grou,ed by the same ,atient regis-tration grou,s used for recording and re,orting+ hich dierentiate ne ,atients

from those ho ha9e had ,rior treatment" ?egistration grou,s for ,re9iously treated,atients are based on the outcome of their ,rior treatment course: failure+ rela,se and

default 5see Cha,ter &8"

) 2ee Global Drug Facility+ "sto,tb"org#gdf#drugsu,,ly#@ualityYsourcingY,rocess"as,"



32


?ecommended regimens for dierent ,atient registration grou,s are shon in Tables"&+ " and "!" $ore details on the e9idence and Eudgements underlying the recom-mended regimens are described in *nneA &"

3.5 ne/ *atients

.e ,atients are de6ned as those ho ha9e no history of ,rior T% treatment or horecei9ed less than ) month of anti-T% drugs 5regardless of hether their smear or

culture results are ,ositi9e or not8 5see section &"78"

)(*(- new patients presumed or &nown to have drug$susceptible TB

.e ,atients are ,resumed to ha9e drug-susce,tible T% ith to eAce,tions:

XWhere Xhere is a high ,re9alence of isonia1id resisXance in ne ,aXienXs 5see sec-tion "/"&8"

or

X 0f Xhey ha9e de9elo,ed acXi9e T% aer =non conXacX iXh a ,aXienX documenXedto ha9e drug-resistant T%< they are li=ely to ha9e a similar drug resistance ,attern

to the source case 578+ and D2T should be carried out at the start of treatment"While D2T results of the ,atient are aaited+ a regimen based on the D2T of the

,resumed source case should be started"

The &-month rifam,icin regimen 5&H?K#7H8 is associated ith more rela,ses anddeaths than the 7-month rifam,icin regimen 5&H?K#!H?8 538"WHO therefore rec-

ommends the folloing for ne ,atients ,resumed or =non to ha9e drug-susce,ti-ble T%" 52ee also 2tandard 4 of the 02TC 58"8





?emar= a:?ecommendation )") also a,,lies to eAtra,ulmonary T% eAce,t T% of the central ner9ous system+ bone or Eoint for hich some eA,ert grou,s suggest

longer thera,y 5see Cha,ter 48"

?emar= b:WHO recommends that national T% control ,rogrammes ,ro9ide su-,er9ision and su,,ort for all T% ,atients in order to ensure com,letion of the full

course of thera,y"

?emar= c:WHO recommends drug resistance sur9eys 5or sur9eillance8 for moni-

toring the im,act of the treatment ,rogramme+ as ell as for designing standardregimens"



33




0n terms of dosing fre@uency for H0-negati9e ,atients+ the systematic re9ie foundlittle e9idence of dierences in failure or rela,se rates ith daily or three times ee=-

ly regimens 538"Hoe9er+ ,atients recei9ing three times ee=ly dosing throughoutthera,y had higher rates of ac@uired drug resistance than ,atients ho recei9eddrugs daily throughout treatment" 0n ,atients ith ,re-treatment isonia1id resist-

ance+ three times ee=ly dosing during the intensi9e ,hase as associated ithsigni6cantly higher ris=s of failure and ac@uired drug resistance than daily dosing

during the intensi9e ,hase" 5Treatment regimens for T% ,atients li9ing ith H0 are

discussed in detail in Cha,ter /"8L Recommendation 2.1

Where!er #easi)le* the optimal dosing #re+uency #or new patients with pulmo,

nary T is daily throughout the course o# therapy




New patients with pulmonary T may recei!e a daily intensi!e phase #ol,lowed )y three times weely continuation phase /2HR%&'(HR pro!ided

3

that each dose is directly o)ser!ed

5Conditional#High or moderate grade of e9idence88


Three times weely dosing throughout therapy /2HR%& '(HR is anoth,3 3

er alternati!e to Recommendation 2.1* pro!ided that e!ery dose is directly

o)ser!ed and the patient is NOT li!ing with H45 or li!ing in an H45,pre!,

alent setting


?emar= a: Treatment regimens for T% ,atients li9ing ith H0 or li9ing inH0-,re9alent settings are discussed in ?ecommendation ! and Cha,ter /"

?emar= b:0n terms of dosing fre@uency for H0-negati9e ,atients+ the sys-tematic re9ie found little e9idence of dierences in failure or rela,se rates

ith daily or three times ee=ly regimens 538"Hoe9er+ rates of ac@uired drug

resistance ere higher among ,atients recei9ing three times ee=ly dosingthroughout thera,y than among ,atients ho recei9ed daily drug administra-tion throughout treatment" $oreo9er+ in ,atients ith ,retreatment isonia1id

resistance+ three times ee=ly dosing during the intensi9e ,hase as associ-




3%


ated ith signi6cantly higher ris=s of failure and ac@uired drug resistance thandaily dosing during the intensi9e ,hase"

There is insuScient e9idence to su,,ort the eScacy of tice ee=ly dosing through-

out thera,y 538"L Recommendation 2.2




?emar=: The a9ailable e9idence shoed e@ui9alent eScacy of daily intensi9e-,hase dosing folloed by to times ee=ly continuation ,hase 538"Hoe9er+ tice

ee=ly dosing is not recommended on o,erational grounds+ since missing onedose means the ,atient recei9es only half the regimen"

Tables "&a and "&b ,resent standard treatment regimen and dosing fre@uency forne T% ,atients"

Table )(2a STAndArd regimenS for new TB pATienTS

"presumed! or &nown! to have drug$susceptible TB#

Intensive *hase treatment Continuation *hase

2 months of HrZe a 4 months of Hr

a wHo no longer recommends omission of ethambutol during the intensive phase of treatment for

patients with non$cavitary! smear$negative pTB or epTB who are &nown to be Hi'$negative( in tuber$

culous meningitis! ethambutol should be replaced by streptomycin(

H = isoniaid! r = rifampicin! Z = pyrainamide! e = ethambutol! S = streptomycin

Table )(2b doSing frequency for new TB pATienTS

dosing !re0uency Comment

daily daily optimal

daily Three times per wee& Acceptable alternative for any new TB patient

receiving directly observed therapy

Three times per wee& Three times per wee& Acceptable alternative provided that the

patient is receiving directly observed therapy

and is not living with Hi' or living in an Hi'$

prevalent setting "See chapter *#

Note+ daily "rather than three times wee&ly# intensive$phase dosing may help to prevent acquired drug

resistance in TB patients starting treatment with isoniaid resistance "see section )(*(2#(



35

)(*(2 Settings with high levels of isoniaid resistance in new patients

When ne ,atients ith isonia1id-resistant T% start their treatment+ outcomesare orse than for ,atients ith isonia1id-susce,tible T%+ e9en ith the 7-month

rifam,icin regimen 538" The global eighted mean of any isonia1id resistance 5eA-cluding $D?8 is 3"!V in ne ,atients 548" Thus+ a signi6cant ,ro,ortion of thene T% cases in many regions of the orld ha9e a ris= of ,oor treatment outcomes

because of their ,retreatment isonia1id resistance"

The folloing ea= recommendation a,,lies to countries here isonia1id susce,-tibility testing in ne ,atients is not done 5or results are not a9ailable8 before the

continuation ,hase begins"

L Recommendation 3

4n populations with nown or suspected high le!els o# isoniazid resistance* newT patients may recei!e HR& as therapy in the continuation phase as an accept,



Gi9en the ,otential bene6t 5(8 and lo ris= of toAicity from ethambutol+ the ,ressingneed to ,re9ent $D? arrants this recommendation" Hoe9er+ the recommenda-

tion is conditional+ for the reasons eA,lained in more detail in *nneA &" The mosteecti9e regimen for the treatment of isonia1id-resistant T% is not =non" There is

inade@uate e9idence to @uantify the ability of ethambutol to ,rotect rifam,icinQin ,atients ith ,re-treatment isonia1id resistance" The e9idence for ocular toAic-

ity from ethambutol as not systematically re9ieed for this re9ision+ but the ris=of ,ermanent blindness eAists" Further research 5see *nneA /8 is therefore urgentlyneeded to de6ne the le9el of isonia1id resistance that ould arrant the addition of ethambutol 5or other drugs8 to the continuation ,hase of the standard ne ,atientregimen in T% ,rogrammes here isonia1id drug susce,tibility testing is not done

5or results are not a9ailable8 before the continuation ,hase begins"

Daily 5rather than three times ee=ly8 intensi9e-,hase dosing may also hel, to ,re-9ent ac@uired drug resistance in T% ,atients starting treatment ith isonia1id resist-

ance" The systematic re9ie 538 found that ,atients ith isonia1id resistance treatedith a three times ee=ly intensi9e ,hase had signi6cantly higher ris=s of failure and

ac@uired drug resistance than those treated ith daily dosing during the intensi9e,hase"

Table " ,resents standard treatment regimens for ne ,atients in settings ith highisonia1id resistance"




3)


Table )() STAndArd regimenS for new TB pATienTS

"in settings where the level of isoniaid resistance among new TB cases

is high and isoniaid susceptibility testing is not done "or results are not

available# before the continuation phase begins#Intensive *hase treatment Continuation *hase

2 months of HrZe 4 months of Hre

3.) revious#y treated *atients and mu#tidrug resistance

Pre9ious T% treatment is a strong determinant of drug resistance 5)'8+ and ,re9iouslytreated ,atients com,rise a signi6cant ,ro,ortion 5)V8 of the global T% noti6ca-

tions in &''3"

Of all the forms of drug resistance+ it is most critical to detect multidrug resistance5$D?8 because it ma=es regimens ith 6rst-line drugs much less eecti9e 5))8 andresistance can be further am,li6ed 5)&8"Prom,t identi6cation of $D? and initiation

of $D? treatment ith second-line drugs gi9es a better chance of cure and ,re9entsthe de9elo,ment and s,read of further resistance" %ecause of its clinical signi6cance+

$D? 5rather than any drug resistance8 is used to describe the retreatment ,atientgrou,s belo"

*t the global le9el+ )/V of ,re9iously treated ,atients ha9e $D? 548+ hich is 69etimes higher than the global a9erage of V in ne ,atients 5Figure ")8" 9en in *fri-ca+ the WHO region thought to ha9e the loest le9el of $D? in retreatment ,atients+

a signi6cant ,ro,ortion 57V8 of retreatment ,atients ha9e $D?-T% 548") 0f their $D?is not detected and treated ith second-line drugs+ these ,atients ill suer ,oor

outcomes and s,read $D? in their communities"

WHO sur9eillance data from )' countries found the le9el of $D? to be &V in,atients returning after defaulting or rela,sing and signi6cantly higher 5!(V8 in,atients hose ,rior treatment has failed 5Figure "&8" Other studies sho $D? le9els&

of u, to 4'('V in ,atients hose ,rior treatment courses ha9e failed 5)'̀ 8"$od-elling described in *nneA & ,redicts that+ hen a 6rst course of treatment contain-ing 7 months of rifam,icin fails+ /'(!V of ,atients ha9e $D?-T% 5com,ared ith

!/7V of ,atients u,on failure of a regimen containing & months of rifam,icin8"

$any factors in[uence the le9el of $D? in ,re9iously treated ,atients+ and le9elsare li=ely to 9ary idely by setting" *ssignment of the retreatment ,atient grou,s to

medium 9s high li=elihood of $D? may therefore need to be modi6ed according tocountry-s,eci6c data on similar grou,s of ,atients+ as ell as other factors discussed

in section "4 belo")Of !7 countries in *frica+ 7 ha9e re,orted drug resistance data since &''&< && countries 5re,resenting

3&V of the regionBs cases8 ha9e re,orted data since )((! 5/+ ," ('8"& These are the only )' countries that re,orted drug resistance sur9eillance data by subcategory of re-

treatment cases since )((3"



3+


figure )(- weigHTed meAn of mdr$TB in new And reTreATmenT TB cASeS

from drug reSiSTAnce Sur'eyS! -::45288; a

a Source+ Anti-tuberculosis drug resistance in the orld! "ourth global re#ort ( geneva! world Health orga$

niation "2889# "8#(b data from -8* countries or -2; settings(c data from :4 countries or -8: settings(

>ew

:2 89* cases b

?etreatment

-9 9;) cases c

2.9;

15.3;

>ot @?

@?

8

28

48

78

98

-88

er cent

figure )(2 mdr in reTreATmenT TB cASeS from drug reSiSTAnce Sur'eySAnd Sur'eillAnce in -8 counTrieS! -::;5288; a

a Source+ van gemert w et al( M$% among sub-categories o" #re&iously treated '( cases! an analysis

in )2 settings( resented at+ 48th Corld Donference on Eung Health! )5; ecember 288:! Dancun!

me%ico(b data from -2 settings in -8 countries(

29) cases b 289 cases b

>ot @?

@?

?elapses Failures

287 cases b

efaulters

32;

%9;

32;

er cent

8

28

48

78

98

-88



3,


3.+ Standard regimens !or *revious#y treated *atients

TheGlobal Plan to 2to, T% &''7&')/sets a target of all ,re9iously treated ,atientsha9ing access to D2T at the beginning of treatment by &')/ 5)38" The ,ur,ose is to

identify $D? as early as ,ossible so that a,,ro,riate treatment can be gi9en" 52eealso 2tandard )) of the 02TC 58"8


;pecimens #or culture and drug suscepti)ility testing :;T should )e o)tained

#rom all pre!iously treated T patients at or )e#ore the start o# treatment. :;T


The a,,roach to the initiation of retreatment de,ends on the countryBs laboratoryca,acity+ s,eci6callyhen5or if8 D2T results are routinely a9ailable for the indi9id-

ual ,atient" Countries using ra,id molecular-based D2T 5)4+)(8 ill ha9e results forrifam,icin#isonia1id a9ailable ithin )& days< these results can be used in deciding

hich regimen to start for the indi9idual ,atient 5section "3")8"

Msing con9entional D2T methods yields results ithin ee=s 5for li@uid media8 ormonths 5for solid media8" %ecause of this delay+ countries using con9entional meth-

ods ill need to start an em,irical regimen hile D2T results are aaited" The choiceof em,irical retreatment regimens is discussed in section "3"& belo"

Where D2T is not yet routinely a9ailable for indi9idual retreatment ,atients+ an in-

terim a,,roach could be im,lemented hile the country is strengthening its labora-tory system"

For many countries+ drug resistance sur9eillance or sur9eys sho that ,atients hose,rior course of thera,y has failed ha9e a high li=elihood of $D? 5es,ecially if the

regimen contained 7 months of rifam,icin+ as described in *nneA &8" Patients hose,rior course of thera,y has failed should therefore recei9e an em,irical $D? regi-

men" Drug resistance sur9eillance or sur9eys often sho that those rela,sing or re-turning after default ha9e a medium or lo li=elihood of $D?< such ,atients can

recei9e the retreatment regimen of 6rst-line drugs" Hoe9er+ le9els of $D? in dier-ent ,atient registration grou,s 9ary by setting")

0t must be noted+ hoe9er+ that the retreatment regimen using 6rst-line drugs is notsu,,orted by e9idence deri9ing from clinical trials" 0t as designed ,rimarily for use

in settings ith lo ,re9alence of initial drug resistance and in ,atients ,re9iouslytreated ith a regimen that included rifam,icin for the 6rst & months 5&'8"

The assum,tion that ,atients hose treatment has failed ha9e a high li=elihood of $D? 5and rela,se or defaulting ,atients ha9e a medium li=elihood of $D?8 may

)0f drug resistance sur9eys sho that ,atients rela,sing or returning after default ha9e high le9els of $D?+ they ill need an $D? regimen instead" 2imilarly+ if the country data sho that le9els of $D?

are lo in ,atients ho failed their ,re9ious treatment+ the .TP may decide to administer retreatmentregimens ith 6rst-line drugs" 2ee section "4 for further details"



39

need to be modi6ed according to both the le9el of $D? found in these ,atient regis-tration grou,s and the considerations discussed in section "4 5belo8"

2e9eral other considerations 5also described in section "48 ill ha9e an im,act on the

le9el of $D? the .TP designates as highQ in a gi9en country" 52ee also 2tandard )&of the 02TC 58"8

Countries ill need to use a miA of a,,roaches if they are in transition+ here someareas of the country do not yet ha9e D2T results routinely a9ailable and others do+ or

some laboratories use ra,id and others con9entional D2T methods"

)(;(- previously treated patients in settings with rapid dST

With line ,robe assays+ $D? can be essentially con6rmed or eAcluded ithin )&)

days+ hich allos the results to guide the regimen at the start of thera,y"&


4n settings where rapid molecular,)ased :;T is a!aila)le* the resultsshould guide the choice o# regimen

The use of ra,id molecular-based tests is discussed in more detail in section "4")belo"

)(;(2 previously treated patients in settings where conventional dST results are

routinely available for individual patients

Obtaining s,ecimens for con9entional culture and D2T should not delay the start of thera,y" m,irical regimens+ often based on drug-resistance sur9eillance data+ are

used hile the results of con9entional D2T 5li@uid or solid media8 are aaited+ andshould be started ,rom,tly" This is es,ecially im,ortant if the ,atient is seriously ill

or the disease is ,rogressing ra,idly" Placing a ,atient on an em,iric regimen ,end-ing D2T is done to a9oid clinical deterioration" *lso+ once em,iric thera,y begins to

render the ,atient less infectious+ the ris= of transmission to contacts decreases"

While aaiting the results of con9entional D2T+ WHO recommends administeringan em,iric $D? regimen for ,atient grou,s ith a high li=elihood of $D?+ and the!

retreatment regimen ith 6rst line drug regimen for ,atient grou,s ith medium orlo li=elihood of $D? 5Table "!8"

)Line ,robe assays detect resistance to rifam,icin alone or in combination ith isonia1id resistance"O9erall high accuracy for detection of $D? is retained hen rifam,icin resistance alone is used as a

mar=er for $D? 5)(8"& From s,utum sam,les or from bacterial cultures deri9ed from those s,ecimens"

0n some indi9idual ,atients ho ha9e been treated multi,le times+ aiting to start treatment until D2Tresults are a9ailable may be ,rudent ,ro9ided that the ,atients are clinically stable and transmission tocontacts is ,re9ented" 0n most countries+ hoe9er+ ade@uate infection control measures are not yet in

,lace"!Guidance on designing a countryBs standard $D? regimen is ,ro9ided in Cha,ter 3 of this document+

and in Cha,ter 3 of Guidelines for the ,rogrammatic management of drug-resistant T%578"




%-



4n settings where rapid molecular,)ased :;T results are not routinely a!aila)le

to guide the management o# indi!idual patients* empiric treatment should )e

started as #ollows$


T patients whose treatment hasfailed1or other patient groups with high

lielihood o# multidrug,resistant T =:R should )e started on an empiri,

cal =:R regimen

?emar= a:0n the absence of culture and D2T results+ the ,atient should be clini-cally e9aluated before the $D? regimen is administered"

?emar= b:Other eAam,les of ,atients ith high li=elihood of $D?-T% are

those rela,sing or defaulting after their second or subse@uent course of treat-ment" 2ee also section "4"&"


T patients returning a#terdefaultingorrela,sing#rom their 9rst treat,


2HR%&;'1HR%&'8HR& i# country,speci9c data show low or medium le!els

o# =:R in these patients or i# such data are not a!aila)le

?emar=:When D2T results become a9ailable+ regimens should be adEusteda,,ro,riately"

)(;() previously treated patients in settings where dST is not routinely available for

individual patients

0n the many countries that still lac= the laboratory ca,acity to routinely conduct D2Tfor each ,re9iously treated ,atient 5or here results arri9e too late to guidethera-,y8+ it is urgent to strengthen laboratory ca,acity" For countries ithout suScient

domestic funding+ 6nancial assistance is a9ailable from the Global Fund to Fight

*0D2+ Tuberculosis and $alaria+ as ell as from M.0T*0D or other international6nancing mechanisms" Technical assistance in laboratory strengthening is a9ailable

from WHO+ Global Laboratory 0nitiati9e and other ,artners"

9en though D2T is not yet routinely a9ailable for indi9idual ,atient managementin these countries+ the .TP may be able to collect or access some information on

le9els of $D?-T% in ,re9iously treated ,atients+ by using data from a drug resistancesur9ey+ from a national or su,ranational reference laboratory+ or from a referral or

research centre 5see section "4"&8" These data are critical for ascertaining the le9el of

)Failures in a ell-run .TP should be infre@uent in the absence of $D?-T%" 0f they do occur+ they aredue either to $D?-T% or to ,rogramme factors such as ,oor DOT or ,oor drug @uality" 0f drug resist-ance data from failure ,atients are a9ailable and these sho lo or medium le9els of $D?+ ,atients

should recei9e the retreatment regimen outlined in 3""&+ and e9ery eort should be made to addressthe underlying ,rogrammatic issues"



%1

$D? in retreatment ,atients" For eAam,le+ the results of re,resentati9e drug resist-)

ance sur9eys may identify a grou, of ,atients among hom a 9ery high ,ercentageha9e $D?+ hich could Eustify the use of $D? regimens in all ,atients in the grou,

5e9en if indi9idual D2T is not a9ailable8 578" The .TP manager is encouraged toobtain technical assistance from the Green Light Committee 5see section "4"8"

0f a 9ery high le9el of $D? is documented in a s,eci6c grou, 5such as ,atients hoha9e failed a retreatment regimen8+ the .TP manager should urgently see= means toroutinely obtain D2T on all such ,atients at the start of treatment+ in order to con6rm

or eAclude $D?" 0f this cannot yet be achie9ed ith any in-country laboratory+ .TPsshould ma=e arrangements to send the s,ecimens from these ,atients to a su,rana-

tional reference or other international laboratory for D2T hile the country ra,idlybuilds domestic laboratory ca,acity"

* country may face a short delay before a domestic or an international laboratory can,erform D2T on s,ecimens from ,atients ho are members of a grou, shon to ha9e

9ery high le9els of $D?-T%" 0n these eAce,tional circumstances+ an .TP may con-sider a short-term ,olicy of directly starting such ,atients on an em,irical $D?-T%

regimen hile aaiting con6rmation of isonia1id and rifam,icin resistance 5last roof Table "!8 578"This is atem,orary measurethat can be im,lemented only if culture

and D2T can be arranged in the 6rst fe months of $D? treatment in each enrolled,atient" 0t is essential to con6rm the ,resence of $D?+ and to monitor the res,onse

to treatment" 5Grou,s of ,atients hose li=elihood of $D? is medium or lo illrecei9e the 4-month retreatment regimen ith 6rst-line drugs"8





?emar=:0f D2T results become a9ailable+ regimens should be adEusted a,,ro,ri-ately"


NT?s should o)tain and use their country,speci9c drug resistance data on #ail,

ure* relapse and de#ault patient groups to determine the le!els o# =:R

?emar=:Country-s,eci6c drug resistance data should include data strati6edby ty,e of regimen gi9en for the ,atientBs 6rst course of T% treatment 5i"e" & 9s

7months of rifam,icin8"

) This information is also needed to determine the ,atterns of $D?+ so that a standard $D? regimencan be chosen for em,irical treatment of ,atients ith high li=elihood of ha9ing $D?"




%2


3. , overa## considerations in se#ecting a country<s standard regimens

.ational T% control ,rogrammes ill need three standard regimens:

ne ,atient regimenQ: the regimen containing 7 months of rifam,icin:

&H?K#!H?)

retreatment regimen ith 6rst-line drugsQ: &H?K2#)H?K#/H?&

$D? regimenQ"

To im,lement these regimens in the country+ the .TP needs to consider the follo-ing factors:

a9ailability of results of con9entional or ra,id molecular-based D2T to guidemanagement of indi9idual ,atients<

le9el of drug resistance in the countryBs ne and ,re9iously treated ,atients< number of $D?-T% ,atients the ,rogramme has the ca,acity to enrol and

treat< the short-term ris= of dying from $D?-T% due to concomitant conditions

5es,ecially H0+ discussed in Cha,ter /8< a9ailability of ,atient su,,ort and su,er9ision 5discussed in Cha,ter 78"

$any of these factors de,end on a9ailable resources in the country+ ,articularly thea9ailability of D2T and $D?-T% treatment" %ecause these essential elements of the

2to, T% 2trategy are not yet fully in ,lace throughout the orld+ this cha,ter ,ro9ides

guidance on interim a,,roaches"

Table "! belo ,resents suggestions for ho the .TP manager can ta=e account of these factors hen selecting the standard regimens for de6ned ,atient grou,s"

)(9(- Availability of dST results to guide management of individual patients+

conventional and rapid methods

4deally* :;T is done #or all patients at the start o# treatment* so thatthe mostappropriate therapy #or each indi!idual can )e determined" Hoe9er+ the goal of

uni9ersal access to D2T has not yet been reali1ed for most of the orldBs T% ,atients"While countries are eA,anding laboratory ca,acity and im,lementing ne ra,id

tests 5see belo8+ WHO recommends that s,utum s,ecimens for testing susce,tibil-ity to isonia1id and rifam,icin be obtained from the folloing ,atient grou,s at the

start of treatment:

X*ll ,re9iously XreaXed ,aXienXs 5)3+&)+&&8"The highest le9els of $D? are found in,atients hose ,rior course of thera,y has failed 578"

X*ll ,ersons li9ing iXh H0 ho are diagnosed iXh acXi9e T%+ es,ecially if Xheyli9e in areas of moderate or high $D? ,re9alence" 0t is essential to detect $D?as soon as ,ossible in ,ersons li9ing ith H0+ gi9en their high ris= of mortality

) With or ithout ethambutol in the continuation ,hase 5see section "/"&8"& Countries ith ra,id molecular-based D2T ill not need this regimen"



%3


Table )(4 STAndArd regimenS for pre'iouSly TreATed pATienTS

depending on the availability of routine dST to guide the therapy of

individual retreatment patients

dS #ie#ihood o! mdr 8*atient registration grou* a

routinely available for

previously treated patients

High "failure #b medium or low "relapse!

default#

rapid molecular$based

method

dST results available in -52 days con0rm or e%clude mdr to

guide the choice of regimen

conventional method while awaiting dST results+ c

empirical mdr regimen

%egimen should be modi*ed

once $+' results are a&ailable.

2HrZeS1HrZe1*Hre


once $+' results are a&ailable(

none "interim# empirical mdr regimen


once $+' results or $%+ data

are a&ailable(

2HrZeS1HrZe1*Hre for full

course of treatment(


once $+' results or $%+ data

are a&ailable(

a The assumption that failure patients have a high li&elihood of mdr "and relapse or defaulting patients a

medium li&elihood# may need to be modi0ed according to the level of mdr in these patient registration

groups! as well considerations discussed in section )(9(b And other patients in groups with high levels of mdr( one e%ample is patients who develop active TB

after &nown contact with a patient with documented mdr$TB( patients who are relapsing or returningafter defaulting from their second or subsequent course of treatment probably also have a high li&eli$

hood of mdr(c regimen may be modi0ed once dST results are available "up to 25) months after the start of treat$

ment#(

Notes+

-( A countryGs standard mdr regimen is based on country$speci0c dST data from similar groups of pa$

tients "see chapter ;#(

2( in the countryGs standard regimens! the 9$month retreatment regimen should not be .augmented/ by a

uoroquinolone or an in3ectable second$line drug this practice 3eopardies second$line drugs that are

critical treatment options for mdr patients( Second$line drugs should be used only for mdr regimensand only if quality$assured drugs can be provided by doT for the whole course of therapy( in addition!

there must be laboratory capacity for cultures to monitor treatment response! as well as a system for

detecting and treating adverse reactions "see section )(9() on the green light committee initiative#

before embar&ing on mdr$TB treatment(

should they ha9e $D?-T%" 2ome ,rogrammes recommend D2T for H0-infected T% ,atients ith CD! counts belo &'' cells#mm 5 78"

XPersons ho de9elo, acXi9e T% aer =non eA,osure Xo a ,aXienX iXh documenX-ed $D?-T%"

X*ll ne ,aXienXs in counXries here Xhe le9el of $D?-T% in ne ,aXienXs is ZV5&8"



%%


0n addition to the indications listed abo9e for D2Tat the startof treatment 5or re-treatment8+ WHO recommends that D2T be ,erformingduringtreatment in the fol-loing situation:

X.e and ,re9iously XreaXed ,aXienXs ho remain s,uXum smear-,osiXi9e aX Xhe endof the intensi9e ,hase should submit another s,ecimen for smear microsco,y the

folloing month" 0f that s,ecimen is also smear-,ositi9e+ culture and D2T shouldbe underta=en 5see ?ecommendation /" in Cha,ter !8" This ill allo a result to

be a9ailable earlier than the 6fth month of treatment"

Com,rehensi9e systems for managing the @uality of laboratory ser9ices+ includinginternal @uality control and eAternal @uality assurance+ are mandatory" Laboratories

should follo standardi1ed ,rotocols for good laboratory ,ractice+ technical ,roce-

dures and biosafety+ in com,liance ith international standards 578" Documentary,roof of sustained technical ,ro6ciency in D2T is essential+ and lin=s ith su,rana-tional T% reference laboratories to ensure D2T @uality are strongly encouraged" 0t is

also im,ortant that a,,ro,riate s,ecimens be obtained and ra,idly trans,orted tothe laboratory" %ecause laboratory errors or discre,ant results may occur+ the clinical

situation must be ta=en into account in inter,reting the results of in 9itro D2T"

,on&entional $+'

WHO has endorsed the use of li@uid culture and ra,id s,ecies identi6cation as ,ref-

erable to solid culture-based methods alone" Li@uid culture and ra,id s,ecies iden-ti6cation should be based on a country-s,eci6c com,rehensi9e ,lan for laboratory

ca,acity strengthening and im,lemented in a ste,-ise manner" Li@uid systems aremore sensiti9e for detecting mycobacteria and may increase the case yield by)'Vcom,ared ith solid media" Li@uid systems may also yield D2T results in as little as

)' days+ com,ared ith &4R!& days using con9entional solid media")

Longer delays in recei9ing D2T results mean longer em,irical treatment+ hich hassigni6cant disad9antages:

XWiXh em,irical use of Xhe reXreaXmenX regimen iXh rsX-line drugs+ ,aXienXshose D2T e9entually con6rms $D? ill ha9e been inade@uately treated hile

aaiting D2T results" Conse@uences could include continued s,read of $D? andam,li6cation of resistance to include ethambutol"

XWiXh em,irical use of $D? regimens+ ,aXienXs hose D2T e9enXually rules ouX$D? ill ha9e been eA,osed to toAic drugs they did not need hile aaiting D2T

results" Conse@uences could include ad9erse drug eects and an increased ris= of defaulting from treatment"

) 2ee "ho"int#tb#dots#laboratory#,olicy#en#indeA"html



%5

%a#id $+'

0n contrast to con9entional methods+ molecular-am,li6cation assays such as line,robe assays allo detection of rifam,icin resistance 5alone or in combination ith

isonia1id8 ithin days of s,utum s,ecimens being obtained from the ,atient 5and canalso be used on cultures obtained from ra,id li@uid culture systems8" Patients ith$D?-T% can a9oid delays in starting an $D? regimen+ and T% ,atients ithout

$D? ill a9oid unnecessary second-line drug treatment" WHO strongly encouragesthe use of ra,id molecular 5and culture-based8 D2T in smear-,ositi9e ,ersons li9ing

ith H0 578"

WHO recommends that ministries of health decide on line ,robe assays for ra,id de-tection of $D?-T% ithin the conteAt of country ,lans for a,,ro,riate managementof $D?-T% ,atients< ,lans should also include the de9elo,ment of country-s,eci6c

screening algorithms and timely access to @uality-assured second-line anti-T% drugs5&!8"

Line ,robe assays ha9e been ade@uately 9alidated in direct testing of s,utum smear-,ositi9e s,ecimens+ as ell as on isolates of $" tuberculosiscom,leA gron from

smear-negati9e and smear-,ositi9e s,ecimens" Direct use of line ,robe assays onsmear-negati9e clinical s,ecimens is not recommended" *do,tion of line ,robe as-

says does not eliminate the need for con9entional culture and D2T ca,ability< cultureremains necessary for de6niti9e diagnosis of T% in smear-negati9e ,atients+ hile

con9entional D2T is re@uired to determine drug susce,tibility to drugs other thanrifam,icin and isonia1id" *dditional guidance on selecting and im,lementing ra,-

id drug susce,tibility tests can be found on the WHO eb site at: "ho"int#tb#featuresYarchi9e#mdrtbYra,idYtests#en#indeA"html

)(9(2 level of drug resistance in the countryGs new and previously treated patients

Countries re,orting a,,roAimately half the orldBs T% cases ha9e conducted at leastone drug resistance sur9ey since )((! 548" These results+ together ith estimates of

$D?-T% le9els in all countries+ are a9ailable on the WHO eb site at: "ho"int#tb#featuresYarchi9e#drsre,ortYlaunchY&7feb'4#en#indeA"html

Ne #atients

Drug resistance information is critical for managing ne ,atients and selecting thecountryBs standard regimen for ne ,atients:

X0f counXry daXa 5or WHO esXimaXes8 sho XhaX more Xhan V of ne ,aXienXs ha9e$D?+ D2T should be obtained at the start of thera,y for all ne ,atients 5see sec-

tion "4")8"

X$any counXries ha9e a high le9el of isonia1id resisXance in ne ,aXienXs buX donot ha9e drug susce,tibility results for isonia1id by the time of the continuation

,hase" 0n these countries+ the .TP may select an isonia1id#rifam,icin#ethambutol




%)


continuation ,hase for the standard regimen to be used for all ne ,atients+ asdiscussed in section "/"&"

re&iously treated #atients*s discussed in section "7 abo9e+ the .TP needs to re9ie country-s,eci6c data to9erify+ or modify+ the assignment of failure ,atients to high li=elihood of $D? 5Table

"!8and ,atients returning after rela,se or default to medium or lo li=elihood of $D?" %oAes ")+ "& and " ,ro9ide eAam,les of ho these data may be used"

While WHO recommends that D2T be ,erformed on all ,re9iously treated cases 5&&8+systems that ill yield this critical information are not yet in ,lace in most countries"Mntil countries ha9e 6nished establishing the needed laboratory and sur9eillance ca-

,acity+ information on the le9el of $D? in ,re9iously treated ,atients is a9ailablefrom a fe other sources"

The Global Drug ?esistance 2ur9eillance ,roEect includes actual and estimated le9elsof $D? in ,re9iously treated ,atients as a hole+ although sam,le si1es ere usually

too small to yield 9ery ,recise estimates 548"$oreo9er+ only )' countries ha9e meas-ured $D? le9els in subgrou,s of ,re9iously treated ,atients since )((! 5Figure "&8"

*lternati9e sources of data are in-country laboratories+ su,ranational reference labo-ratories+ hos,itals+ treatment centres and research ,roEects" The results must be in-

ter,reted ith caution+ as they re,resent only those ,atients ho ha9e accessed thes,eci6c ser9ices and those institutions here the testing is done" For eAam,le+ the

le9el of $D? found in a hos,ital-based sur9ey in a ca,ital city acce,ting referralsof the most diScult cases is li=ely to be higher than the le9el that ould be found in

unselected ,atients in a remote area"

ox 3.1

An e%Ample of reASSigning pATienT groupS BASed on

counTry$Specific drug reSiSTAnce Sur'ey reSulTS

in country A! a nationwide survey of all previously treated patients showed the followinglevels of mdr in patients+

6 whose prior treatment failed+ :8I

6 who have relapsed+ 9*I

6 returning after default+ )8I

Because relapsing patients have nearly as high a level of mdr as those whose treatment

has failed! country A decides that relapsing patients "while awaiting their dST results#

will receive the countryGs standard empirical mdr regimen( in the national version of

Table )(4 in its nTp manual! country A moves relapse patients from medium to highli&elihood of mdr so they are managed the same way as patients whose prior treatment

has failed "while patients returning after default are treated with the 9$month retreat$

ment regimen with 0rst$line drugs#(



%+

Note on other #atient-s#eci*c ris "actors "or M$%

%y assigning registration grou,s of ,re9iously treated ,atients to high and mediumli=elihood of $D?+ Table "! incor,orates 2tandard )) of the 02TC 58"This standard

recommends that an assessment of the li=elihood of drug resistance be obtained forall ,atients at the start of treatment"

The most critical ,atient-s,eci6c ris= factor for $D?-T% is ,rior T% treatment 5)+)!8"

Nnon contact ith a ,ro9en $D? case is another im,ortant determinant andcan be ascertained by T% ,rogrammes at the time of ,atient registration" Other T%

,atients obser9ed to ha9e ele9ated $D? le9els in certain settings are those 578:

treated in a ,rogramme that o,erates ,oorly<

ith a history of using anti-T% drugs of ,oor or un=non @uality< ho remain s,utum smear-,ositi9e at month & or of treatment 5see Cha,ter

!8< hose ,ri9ate-sector treatment has failed< eA,osed in institutions ith an $D? outbrea= or a high ,re9alence of $D?

5such as certain ,risons or mines8< ith co-morbid conditions associated ith malabsor,tion or ra,id-transit

diarrhoea< li9ing ith H0 5in some settings8< hose ,rior course of thera,y included rifam,icin throughout 5*nneA &8< ha9e ty,e & diabetes mellitus 5&/8"

.TPs may be able to collect sam,les for D2T from some of the ,atient grou,s listedabo9e to determine their le9els of $D?"

)(9() number of mdr$TB patients the programme has the capacity to enrol

The Green Light Committee 5GLC8 0nitiati9e hel,s countries to gain access to @uality-assured second-line drugs at considerably less than mar=et ,rices" The GLC ,ro9ides)

countries ith high-le9el eA,ertise in setting u, and running $D?-T% ,rogrammes+integrated ith routine T% control acti9ities" 0nformation about the GLC a,,lication

,rocess can be found online at: "ho"int#tb#challenges#mdr#greenlightcommittee#en#indeA"html

ProEects intending to treat feer than /' ,atients can use a fast-trac= o,tion to mini-mi1e the time re@uired for the GLC a,,lication ,rocess" Countries ith limited do-

mestic resources for $D? detection and treatment can a,,ly to the Global Fund toFight *0D2+ Tuberculosis and $alaria or other donors for funding"

)0f second-line drugs are used+ the .TP must ensure that they are @uality-assured and can be ,ro9idedby DOT throughout the entire )4&! months it ta=es to treat $D? T%" 0n addition+ laboratory ca,acity

to monitor res,onse to treatment and a system for detecting and treating ad9erse reactions must be in,lace"




%,


*s suScient funding becomes a9ailable+ countries ill ,ro9ide uni9ersal access to$D?-T% treatment" The stage of im,lementation has a bearing on the le9el of $D?

that the country ill use to de6ne highQ+ mediumQ and loQ li=elihood of $D?"

*t the beginning of an $D? ,rogramme+ hen the a9ailability of $D? treatment is9ery limited+ the .TP may chose to include only the 9ery highest ris= ,atients in the

high li=elihood of $D?Q grou, for em,irical $D? treatment hile D2T results areaaited" *s the ,rogramme is scaled u,+ the .TP manager can include more ,atients

ho need $D? treatment" Thus+ there are no absolute thresholds for lo+ moderate+or high li=elihood or le9els of $D?: .TP managers ill de6ne them for their oncountry and ill need to rede6ne them as ,rogress is made toards uni9ersal access

to $D?-T% treatment"

ox 3.2

An e%Ample of ASSigning THe pATienT group wiTH

THe HigHeST mdr le'elS To recei'e empiricAl mdr TreATmenT!

And lATer Adding A pATienT group wiTH THe ne%T HigHeST mdrle'elS! during ScAle$up of mdr$TB TreATmenT

Based on a special survey in one province! country B 0nds an mdr level of :8I in TB

patients whose treatment failed after two or more prior courses( for patients whose 0rst

treatment course failed! the level is 78I( The TB patients in this province are roughly

representative of the whole countryGs TB patients( in country B! dST of isoniaid and

rifampicin is done routinely for individual patients whose previous treatment has failed

but results are typically not available for 4 months(

country B has 3ust begun a green light committee initiative pro3ect and has the

capacity to treat a very limited number of mdr$TB patients( it recommends that patients

whose second or subsequent course of treatment has failed be managed as patients

with a high li&elihood of mdr "as recommended in Table )(4# and receive an empirical

regimen for mdr while dST results are awaited( until the mdr programme is scaled up

further! patients whose 0rst treatment course has failed will be managed as those with a

medium li&elihood of mdr( empirically! they all start the retreatment regimen with 0rst$

line drugs( when dST results are available 4 months later! those con0rmed as having

mdr$TB are changed to the mdr regimen(

Two years later! another drug resistance survey continues to show that 78I of patients

whose 0rst treatment failed have mdr! and their outcomes have been poor when treated

empirically with the retreatment regimen of 0rst$line drugs for the 4 months it ta&es to

obtain dST results( By contrast! treatment with the countryGs standard mdr regimen is

having good success in the patients in whom two or more prior treatment courses have

failed( The country applies for and receives additional support from the global fund to

now use empirical mdr regimens "while awaiting dST results# for patients whose 0rst

treatment course has failed(



%9


ox 3.3

An e%Ample of weigHing THe HArmS And BenefiTS of empiricAl mdr

TreATmenT in A SeTTing of HigH Hi' pre'Alence

in country c! 98I of all TB patients are living with Hi'! and )8I of relapse patients

have mdr( while the country is planning to implement rapid dST! it ta&es an average of

2 months to obtain results using the current conventional methods( The nTp is decid$

ing which empirical regimen to include in the nTp manual for relapse patients for the

2 months it ta&es to obtain dST results(

given the high level of Hi' and the attendant ris&s of early death from untreated mdr$

TB! the nTp decides to recommend that all relapse patients be treated with the countryGs

empirical mdr regimen while dST results are awaited( The bene0t of preventing early

deaths in the )8I of relapse patients who do have mdr is 3udged to be greater than the

possible harms of mdr treatment "during the 2 months awaiting dST results# in thea

;8I of relapse patients who will prove to not have mdr(

a possible harms include drug to%icity! increased li&elihood of patient default! and burden on

patient and programme resources(

)(9(4 Short$term ris& of death from mdr$TB

Clinicians faced ith a 9ery ill T% ,atient sus,ected of ha9ing $D?-T% ill initi-

ate an $D? regimen hile D2T results are ,ending+ e9en if the li=elihood of $D?may be intermediate rather than high" The clinician Eudges that the ris= of toAicity

of the $D? regimen is outeighed by the ,ossible life-sa9ing bene6t of the $D?regimen"

2imilar Eudgements a,,ly to regimen decisions at the le9el of the .TP" 0f ,re9iouslytreated ,atients as a grou, ha9e fre@uent concomitant conditions 5such as H08 that

increase the ris= of short-term death from $D?-T%+ the .TP ill ant to recom-mend an em,irical $D? regimen for more retreatment ,atients hile D2T results

are aaited" 5WHO also recommends the use of ra,id molecular-based tests insmear-,ositi9e ,ersons found to be li9ing ith H0+ as ell as culture-based D2T to

determine additional drug susce,tibility 578"8

)(9(* Availability of patient support and supervision

The a9ailability of good @uality ,atient su,,ort and su,er9ision is essential to im-,lementation of the regimens recommended in this cha,ter" The im,ortance of theca,acity of T% ,rogrammes to ,ro9ide ,atient-centred care is discussed in Cha,ter

7"



5-


re!erences

?ational Pharmaceutical $anagement Plus Program")" $anaging ,harmaceuticalsand commodities for tuberculosis: a guide for national tuberculosis ,rograms"*rling-

ton+ *+ $anagement 2ciences for Health+ &''/"*merican Thoracic 2ociety+ CDC+ 0nfectious Diseases 2ociety of *merica" Treat-&"ment of tuberculosis"$orbidity and $ortality Wee=ly ?e,ort: ?ecommendations and?e,orts+ &''+ /&5??-))8:)33"0nternational 2tandards for Tuberculosis Care 502TC8" + &nd ed" The Hague+ Tuberculo-sis Coalition for Technical *ssistance+ &''("

Connor + ?after .+ ?odgers *" Do 6Aed-dose combination ,ills or unit-of-use ,ac=-!"aging im,ro9e adherence * systematic re9ie"%ulletin of the World Health Organi-1ation+ &''!+ 4&:(/(("

%artace= * et al" Com,arison of a four-drug 6Aed-dose combination regimen ith a/"

single tablet regimen in smear-,ositi9e ,ulmonary tuberculosis"0nternational our-nal of Tuberculosis and Lung Disease+ &''(+ ):37'377"

Guidelines for the ,rogrammatic management of drug-resistant tuberculosis: emer-7"gency u,date &''4" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$# T%#&''4"!'&8"

$en1ies D et al" ect of duration and intermittency of rifam,in on tuberculosis3"treatment outcomes: a systematic re9ie and meta-analysis"Plo2 $edicine+ &''(+7:e)''')!7"*nti-tuberculosis drug resistance in the orld: fourth global re,ort4" " Gene9a+ World

Health Organi1ation+ &''4 5WHO#HT$#T%#&''4"(!8"$itchison D*" %asic mechanisms of chemothera,y"(" Chest+ )(3(+ 3757 2u,,l"8: 33)34)"

s,inal $* et al" Determinants of drug-resistant tuberculosis: analysis of )) coun-)'"tries"0nternational ournal of Tuberculosis and Lung Disease+ &'')+ /:4434("

s,inal $* et al" 2tandard short-course chemothera,y for drug-resistant tuberculo-))"sis: treatment outcomes in 7 countries" ournal of the *merican $edical *ssociation+&'''+ &4:&/3&/!/"

Iuy HT et al" Drug resistance among failure and rela,se cases of tuberculosis: is the)&"standard re-treatment regimen ade@uate0nternational ournal of Tuberculosis andLung Disease+ &''+ 3:7)77"

2ara9ia C et al" ?etreatment management strategies hen 6rst-line tuberculosis)"thera,y fails"0nternational ournal of Tuberculosis and Lung Disease+ &''/+ (:!&)!&("

oshiyama T et al" De9elo,ment of ac@uired drug resistance in recurrent tubercu-)!"losis ,atients ith 9arious ,re9ious treatment outcomes"0nternational ournal of Tuberculosis and Lung Disease+ &''!+ 4:)4"Drobnies=i F et al" Drug-resistant tuberculosis+ clinical 9irulence+ and the domi-)/"nance of the %eiEing strain family in ?ussia" ournal of the *merican $edical *ssocia-

tion+ &''/+ &(:&3&7&3)"Faustini *+ Hall *+ Perucci C*" ?is= factors for multidrug resistant tuberculosis in)7"uro,e: a systematic re9ie" ThoraA+ &''7+ 7):)/4)7"



51

The Global Plan to 2to, T%+ &''7&')/)3" " Gene9a+ World Health Organi1ation+ &''75WHO#HT$#2T%#&''7"/8"

%arnard $ et al" ?a,id molecular screening for multidrug-resistant tuberculosis in a)4"high-9olume ,ublic health laboratory in 2outh *frica"*merican ournal of ?es,ira-

tory and Critical Care $edicine+ &''4+ )33:3433(&"2am 0C et al" $ycobacterium tuberculosis and rifam,in resistance+ Mnited Ningdom")("

merging 0nfectious Diseases+ &''7+ )&:3/&3/("$en1ies D et al" 2tandardi1ed treatment of acti9e tuberculosis in ,atients ith ,re-&'"9ious treatment and#or ith mono-resistance to isonia1id: a systematic re9ie and

meta-analysis"Plo2 $edicine+ &''(+ 7:e)''')/'" The global $D?-T% ^ JD?-T% res,onse ,lan &''3&''4&)" " Gene9a+ World HealthOrgani1ation+ &''3 5WHO#HT$#T%#&''3"438"Guidelines for the sur9eillance of drug resistance in tuberculosis&&" + !th ed" Gene9a+

World Health Organi1ation+ &''( 5WHO#HT$#T%#&''("!&&8"s,inal $+ ?a9iglione $C" From threat to reality: the real face of multidrug-resist-&"ant tuberculosis"*merican ournal of ?es,iratory and Critical Care $edicine+ &''4+)34:&)7&)3"

$olecular line ,robe assays for ra,id screening of ,atients at ris= of $D? T%: ,olicy&!"statement"Gene9a+ World Health Organi1ation+ &''4 5a9ailable at: "ho"int#tb#featuresYarchi9e#,olicyYstatement",df8"Fisher-Hoch 2P et al" Ty,e & diabetes and multidrug-resistant tuberculosis"&/" 2candi-na9ian ournal of 0nfectious Diseases+ &''4+ !':4444("




53

%

$onitoring during treatment

%.1 Cha*ter o"4ectives

This cha,ter describes ho to:

monitor and record the res,onse to treatment+ and decide on actions to ta=e inres,onse to monitoring results<

use cohort analysis to e9aluate treatment outcomes<

manage treatment interru,tion< detect and manage drug-induced toAicity"

%.2 monitoring the *atient

*ll ,atients should be monitored to assess their res,onse to thera,y 52tandard )' of the 02TC 5)88"?egular monitoring of ,atients also facilitates treatment com,letion

and allos the identi6cation and management of ad9erse drug reactions" *ll ,atients+their treatment su,,orters and health or=ers should be instructed to re,ort the

,ersistence or rea,,earance of sym,toms of T% 5including eight loss8+ sym,toms of ad9erse drug reactions+ or treatment interru,tions"

Patient eight should be monitored each month+ and dosages should be adEustedif eight changes" *dditional monitoring and the actions it triggers are discussed

belo for ,ulmonary and eAtra,ulmonary cases treated ith 6rst-line drugs" Formonitoring of ,atients recei9ing second-line drugs+ see Cha,ter 3"

* ritten record of all medications gi9en+ bacteriological res,onse and ad9erse reac-tions should be maintained for e9ery ,atients on the T% Treatment Card 5&8 52tan-

dard ) of the 02TC 5)88"

%. 3 assessing treatment res*onse in ne/ and *revious#y treated

*u#monary " *atients= and acting on the resu#ts

?es,onse to treatment in ,ulmonary T% ,atients is monitored by s,utum smear eA-amination 5see Figures !") and !"& belo8"


7or smear,positi!e pulmonary T patients treated with 9rst,line drugs*

spu,tum smear microscopy may )e per#ormed at completion o# the intensi!e phaseo# treatment




5%


figure 4(- SpuTum moniToring By SmeAr microScopy in new pulmonAry

TB pATienTS

Note+ Jf a patient is found to harbour a multidrug$resistant strain of TB at any time during therapy! treat$

ment is declared a failure and the patient is re$registered and should be referred to an mdr$TB treatment

programme(

months o! treatment

1 2 3 % 5 )

K======== ========L

6K$$$$$$$$$$$$$$$ $$$$$$$$$$$$$$$$ $ $$ $$ $$ $$ $$ $$ $$ $$

6 a

if sm ! obtain

culture! dST b

$ $$ $$$ $$ $$$ $$ $$ L

6 a

if sm ! obtain

culture! dST b

if smear$positive at month 2! obtain sputum again at month )( if smear$positive at month )!obtain culture and dST(

K======== ========L

6"sm #

K$$$$$$$$$$$$$$$

6if sm ! obtain

culture! dST

$$$ $$$ $$ $$ $$ $$ $$ $ $$ $$ $$ $$ $$ $$ $$ $$

6if sm ! obtain

culture! dST b

$ $$ $$$ $$ $$ $$ $$ $$ L

6if sm ! obtain

culture! dST b

,ey+

K========L intensive phase of treatment "HrZe#

K$$$$$$$$$$$$L continuation phase "Hr#

6 sputum 6mear e%amination

sm Smear$positivea omit if patient was smear$negative at the start of treatment and at 2 months(b Smear$ or culture$positivity at the 0fth month or later "or detection of mdr$TB at any point# is de0ned

as treatment failure and necessitates re$registration and change of treatment as described in section

)(;(

figure 4(2 SpuTum moniToring of pulmonAry TB pATienTS recei'ing THe

9$monTH reTreATmenT regimen wiTH firST$line drugS

months o! treatment

1 2 3 % 5 ) + ,

K======== ======== ========L

6if sm !

obtain

culture!

dST

K$$$$$$$$$$$$$$ $$$$$$$$$$$$$$$

6if sm !

obtain

culture!

dST a

$ $$ $$ $$ $$ $$ $$ $$ $ $$ $$ $$ $$ $$ $$ $$ $ $$ $$$ $$ $$$ $$ $ L

6if sm !

obtain

culture!

dST a

,ey+

K========L intensive phase+ 2 months of HrZeS followed by - month of HrZe

K$$$$$$$$$$$$L continuation phase with * months of Hre6 sputum 6mear e%amination

sm Smear$positivea Smear$ or culture$positivity at the 0fth month or later "or detection of mdr$TB at any point# is de0ned

as treatment failure and necessitates reregistration and change of treatment as described in section

)(;(



55

This recommendation a,,lies both to ne ,atients treated ith regimens containing7 months of rifam,icin 5&H?K#!H?8 and to ,re9iously treated ,atients recei9ing

the 4-month retreatment regimen ith 6rst-line drugs 5&H?K2#)H?K#/H?8"2,utum should be collected hen the ,atient is gi9en the last dose of the intensi9e-,hase treatment" The end of the intensi9e ,hase is at & months in ne ,atients and

months in ,re9iously treated ,atients recei9ing the 4-month regimen of 6rst-linedrugs" This recommendation also a,,lies to smear-negati9e ,atients"

2,utum s,ecimens should be collected for smear eAamination at each follo-u, s,u-tum chec=" They should be collected ithout interru,ting treatment and trans,ortedto the laboratory as soon as ,ossible thereafter< if a delay is una9oidable+ s,ecimens

should be refrigerated or =e,t in as cool a ,lace as ,ossible"

2mear status at the end of the intensi9e ,hase is a ,oor ,redictor of hich ne,atients ill rela,se" Hoe9er+ detection of a ,ositi9e s,utum smear remains im,or-)

tant as a trigger for the ,atient assessment outlined belo as ell as for additionals,utum monitoring described in sections !"") and !""&" The ,ro,ortion of smear-

,ositi9e ,atients ith s,utum smear con9ersion at the end of the intensi9e ,hase isalso an indicator of T% ,rogramme ,erformance"

* ,ositi9e s,utum smear at the end of the intensi9e ,hase may indicate any of thefolloing:

the initial ,hase of thera,y as ,oorly su,er9ised and ,atient adherence as,oor< ,oor @uality of anti-T% drugs< doses of anti-T% drugs are belo the recommended range<

resolution is slo because the ,atient had eAtensi9e ca9itation and a hea9y ini-tial bacillary load<

there are co-morbid conditions that interfere either ith adherence or ithres,onse<

the ,atient may ha9e drug-resistant$" tuberculosisthat is not res,onding to

6rst-line treatment< non-9iable bacteria remain 9isible by microsco,y 58"

The ,rogramme should carefully re9ie the @uality of the ,atientBs su,,ort andsu,er9ision and inter9ene ,rom,tly if necessary" Patient treatment records should be

re9ieed ith the res,onsible health care or=er+ and reasons for any interru,tionsshould be eA,lored and addressed 5!8"

0t is unnecessary+ unreliable and asteful of resources to monitor the ,atient by chestradiogra,hy"

)2ystematic re9ie as not ,ublished by the time of ,ublication of this document" G?*D tables area9ailable from WHO u,on re@uest"

%. monIorIn$ durIn$rEamEn



5)


4()(- new pulmonary TB patients

*dditional s,utum monitoring is needed for ne ,atients hose s,utum smear is,ositi9e at the end of the intensi9e ,hase 52tandard )' of the 02TC 5)88"

L Recommendation 8.24n new patients* i# the specimen o)tained at the end o# the intensi!ephasemonth 2 is smear,positi!e* sputum smear microscopy should )e o)tained at

the end o# the third month





The main ,ur,ose of obtaining cultures at this stage is to detect drug resistance ith-out aiting until the 6fth month to change to a,,ro,riate thera,y" 5.ote that treat-)

ment is declared a failure if a ,atient is found to harbour $D?-T% at any ,oint intime during treatment< see Table !")"8

0f the country does not yet ha9e suScient laboratory ca,acity for culture and D2T+additional monitoring of ,atients ho are still smear-,ositi9e at month ill be only

by s,utum smear microsco,y during the 6fth month and during the 6nal month of treatment" 0f either result is ,ositi9e+ treatment has failed+ the ,atient is reregistered

and treatment is changed as described in Cha,ter "

Ne #ulmonary '( #atients ith #ositi&e s#utum smears at the start o" treatment

These ,atients should be monitored by s,utum smear microsco,y at the end of the6fth and siAth months" 0f results at the 6fth or siAth month are ,ositi9e+ a s,utum

s,ecimen should be obtained for culture and D2T" Treatment has failed+ the T% Treat-ment Card is closed 5Outcome treatment failure8 and a ne one is o,ened 5Ty,e of

,atient treatment after failure8" Treatment should follo the recommendations inCha,ter " 0f a ,atient is found to harbour a multidrug-resistant strain of T% at any

,oint of time during thera,y+ treatment is also declared a failure" 2ee Figure !") for amonitoring scheme ith s,utum smear microsco,y"

Ne #ulmonary '( #atients hose s#utum smear microsco#y as negati&e

/or not done at the start o" treatment

0t is im,ortant to rechec= a s,utum s,ecimen at the end of the intensi9e ,hase

incase of disease ,rogression 5due to non-adherence or drug resistance8 or an errorat the time of initial diagnosis 5i"e" a true smear-,ositi9e ,atient as misdiagnosed

)9en if there is e9entually full susce,tibility+ a ,ositi9e culture con6rms ,oor res,onse to treatment+hich necessitates in9estigation and inter9ention"



5+

as smear-negati9e8" Pulmonary T% ,atients hose s,utum smear microsco,y as)

negati9e 5or not done8 before treatment and hose s,utum smears are negati9eat &months need no further s,utum monitoring" They should be monitored clinically<

body eight is a useful ,rogress indicator"

4()(2 previously treated sputum smear$positive pulmonary TB patients receiving

0rst$line anti$TB drugs

2,utum smear eAamination is ,erformed at the end of the intensi9e ,hase of treat-ment 5the rd month8+ at the end of the 6fth month and at the end of treatment 5the

eighth month8" 0f the country has already de9elo,ed suScient laboratory ca,acity+culture and D2T should be ,erformed at the start of treatment and+ if smears are

,ositi9e+ at any of these ,oints in time" 2ee Figure !"& for a monitoring scheme ith

s,utum smear microsco,y"

L Recommendation 8.(

4n pre!iously treated patients* i# the specimen o)tained at the end o# the inten,

si!e phase month 3 is smear,positi!e* sputum culture and drug suscepti)ility



%.% Extra*u#monary "

For ,atients ith eAtra,ulmonary T%+ clinical monitoring is the usual ay of assess-ing the res,onse to treatment 52tandard )' of the 02TC 5)88"*s in ,ulmonary smear-negati9e disease+ the eight of the ,atient is a useful indicator"

%. 5 recording standardied treatment outcomes

*t the end of the treatment course for each indi9idual ,atient+ the District T% OScerrecords the treatment outcome in the District T% ?egister" Table !") shos the de6ni-

tions of standardi1ed treatment outcomes"

%.) Cohort ana#ysis o! treatment outcomes

* cohort is a grou, of ,atients diagnosed and registered for treatment during a s,e-ci6c time ,eriod 5usually one-@uarter of a year8" 9aluation of treatment outcome in

ne ,ulmonary smear-,ositi9e ,atients is used as a maEor indicator of ,rogramme@uality" Outcomes in other ,atients 5retreatment+ ,ulmonary smear-negati9e+ eAtra-

,ulmonary8 are analysed in se,arate cohorts" 5For guidance on cohort analysis of $D?-T% ,atients+ see reference/"8

Cohort analysis is the =ey management tool used to e9aluate the eecti9eness of thenational T% control ,rogramme" 0t enables the identi6cation of ,roblems+ so that the

) 0f the s,utum is found to be smear-,ositi9e+ see ?ecommendations /"& and /" abo9e"




5,


,rogramme managers and sta can institute a,,ro,riate action to o9ercome themand im,ro9e ,rogramme ,erformance" 9aluation of the outcomes of treatment andtrends must be done at ,eri,heral+ district+ regional and national le9els to allo anynecessary correcti9e action to be ta=en" 0t can also identify districts or units that are

,erforming ell and allos for ,ositi9e feedbac= to be ,ro9ided to sta< successful,ractices can then be re,licated elsehere"

Table 4(- definiTionS of TreATmenT ouTcomeS a

outcome definition

cure A patient whose sputum smear or culture was positive at the beginning

of the treatment but who was smear$ or culture$negative in the last

month of treatment and on at least one previous occasion(

Treatment

completed

A patient who completed treatment but who does not have a negative

sputum smear or culture result in the last month of treatment and on at

least one previous occasion b

Treatment failure A patient whose sputum smear or culture is positive at * months or later

during treatment( Also included in this de0nition are patients found to

harbour a multidrug$resistant "mdr# strain at any point of time during

the treatment! whether they are smear$negative or $positive(

died A patient who dies for any reason during the course of treatment(

default A patient whose treatment was interrupted for 2 consecutive months ormore(

Transfer out A patient who has been transferred to another recording and reporting

unit and whose treatment outcome is un&nown(

Treatment success A sum of cured and completed treatment c

a These de0nitions apply to pulmonary smear$positive and smear$negative patients! and to patients with

e%trapulmonary disease( outcomes in these patients need to be evaluated separately(b The sputum e%amination may not have been done or the results may not be available(c for smear$ or culture$positive patients only(

The district#local T% oScer should ,erform cohort analysis of treatment outcomee9ery @uarter-year and at the end of e9ery year" * ty,ical cohort consists of all T%

,atients registered during a @uarter" .e ,atients and subcategories of ,re9iouslytreated ,atients 5rela,ses+ return after default+ failures8 should be analysed as se,arate

cohorts because they ha9e dierent characteristics and eA,ected results" 9aluationof outcome at the end of treatment should be underta=en as soon as ,ossible after the

last ,atient in the cohort com,letes treatment")

This information is transmitted in @uarterly re,orts" *fter local re9ie+ district re-

)Outcomes are routinely e9aluated at the beginning of the @uarter folloing the com,letion of treat-ment by the last ,atient in that cohort"



59

,orts on treatment outcome are forarded to the region each @uarter" The regional#intermediate T% oScer should 9erify that district re,orts are correct+ com,lete and

consistent+ com,ile cohort analysis re,orts on the s,utum smear-,ositi9e ,atientsin the region+ and submit the re,ort to the central unit of the .TP" The .TP com-

,iles cohort analysis re,orts on the smear-,ositi9e T% ,atients registered nationally+e9aluates+ and ,ro9ides feedbac= to the ,rogramme sta"

%.+ management o! treatment interru*tion

2u,,orting ,atients to ,re9ent treatment interru,tion is discussed in Cha,ter 7< thissection co9ers hat to do if treatment is interru,ted"

0f a ,atient misses an arranged a,,ointment to recei9e treatment+ the .TP should

ensure that the ,atient is contacted ithin a day after missing treatment during theinitial ,hase+ and ithin a ee= during the continuation ,hase" The ,atient can betraced using the locating information ,re9iously obtained 5see section 7"/8 578" 0t is

im,ortant to 6nd out the cause of the ,atientBs absence so that a,,ro,riate action canbe ta=en and treatment can continue"

The management of ,atients ho ha9e interru,ted treatment ta=es into considerationse9eral factors+ each of hich+ if ,resent+ ill necessitate further caution and ,rob-

ably additional treatment 538:

Xe ,aXienX is found Xo be smear- or culXure-,osiXi9e u,on reXurning from de-fault"X0nXerru,Xion occurs in Xhe inXensi9e+ raXher Xhan Xhe conXinuaXion+ ,hase"X0nXerru,Xion occurs early 5raXher Xhan laXer8 in Xhe conXinuaXion ,hase"Xe inXerru,Xion is of long duraXion"Xe ,aXienX is immunocom,romised 5li9ing iXh H0 or anoXher condiXion8"Xe ,aXienX had ,oor res,onse Xo XreaXmenX before Xhe inXerru,Xion"XDrug-resisXanX disease is =non or sus,ecXed"

Culture and D2T should be ,erformed u,on return of ,atients ho meet the de6ni-tion in Table !") for default 5interru,ted treatment for at least & consecuti9e months8"

0f laboratory ca,acity ,ermits+ s,ecimens for culture and D2T should also be ob-tained from other ,atients returning after treatment interru,tion"

%. , revention o! adverse e!!ects o! drugs

Health ,ersonnel can ,re9ent some drug-induced side-eects+ for eAam,le isonia1-id-induced ,eri,heral neuro,athy" This usually ,resents as numbness or a tinglingor burning sensation of the hands or feet and occurs more commonly in ,regnant

omen and in ,eo,le ith the folloing conditions: H0 infection+ alcohol de,en-dency+ malnutrition+ diabetes+ chronic li9er disease+ renal failure" These ,atients

should recei9e ,re9enti9e treatment ith ,yridoAine+ )' mg#day along ith theiranti-T% drugs" 5Other guidelines recommend &/ mg#day 538"8




)-


%.9 monitoring and recording adverse e!!ects

$ost T% ,atients com,lete their treatment ithout any signi6cant ad9erse drug ef-fects" Hoe9er+ a fe ,atients do eA,erience ad9erse eects" 0t is therefore im,ortant

that ,atients be clinically monitored during treatment so that ad9erse eects canbe detected ,rom,tly and managed ,ro,erly" ?outine laboratory monitoring is notnecessary"

Health ,ersonnel can monitor ad9erse drug eects by teaching ,atients ho to rec-ogni1e the sym,toms of common eects+ urging them to re,ort if they de9elo, such

sym,toms+ and by as=ing about sym,toms hen ,atients come to collect drugs"

*d9erse reactions to drugs should be recorded on the T% Treatment Card underObser9ationsQ"

$onitoring of ,atients recei9ing second-line drugs is co9ered in Cha,ter 3"

%.1- Sym*tom&"ased a**roach to managing side&e!!ects o! anti&" drugs

The ad9erse eects of essential anti-T% drugs are described in *nneA )" Table !"&shos a sym,tom-based a,,roach to the management of the most common ad-

9erse eects+ hich eects are classi6ed as maEor or minor" 0n general+ a ,atient hode9elo,s minor ad9erse eects should continue the T% treatment and be gi9en sym,-

tomatic treatment" 0f a ,atient de9elo,s a maEor side-eect+ the treatment or the

res,onsible drug is sto,,ed< the ,atient should be urgently referred to a clinician orhealth care facility for further assessment and treatment" Patients ith maEor ad9erse

reactions should be managed in a hos,ital"

4(-8(- management of cutaneous reactions

0f a ,atient de9elo,s itching ithout a rash and there is no other ob9ious cause+ therecommended a,,roach is to try sym,tomatic treatment ith antihistamines and

s=in moisturi1ing+ and continue T% treatment hile obser9ing the ,atient closely" 0f

a s=in rash de9elo,s+ hoe9er+ all anti-T% drugs must be sto,,ed"Once the reaction has resol9ed+ anti-T% drugs are reintroduced one by one+ startingith the drug least li=ely to be res,onsible for the reaction 5rifam,icin or isonia1id8

at a small challenge dose+ such as /' mg isonia1id 58"The dose is gradually increasedo9er days" This ,rocedure is re,eated+ adding in one drug at a time" * reaction after

adding in a ,articular drug identi6es that drug as the one res,onsible for the reac-tion" The alternati9e regimens listed in section !")'"& belo are also a,,licable hen a,articular drug cannot be used because it as im,licated as the cause of a cutaneous

reaction"

4(-8(2 management of drug$induced hepatitis

This section co9ers he,atitis ,resumed to be induced by T% treatment" 5For a discus-sion of T% treatment in ,atients ith underlying li9er disease+ see Cha,ter 4"8



)1


Table 4(2 SympTom$BASed ApproAcH To mAnAging Side$effecTS

of AnTi$TB drugS

Side&e!!ects drug8s *ro"a"#y

res*onsi"#e

management

Ma1or +to# res#onsible drug/s and re"er toclinician urgently

S&in rash with or withoutitching

Streptomycin!isoniaid!rifampicin!pyrainamide

Stop anti$TB drugs

deafness "no wa% onotoscopy#

Streptomycin Stop streptomycin

diiness "vertigo andnystagmus#

Streptomycin Stop streptomycin

Maundice "other causese%cluded#! hepatitis

isoniaid!pyrainamide!rifampicin

Stop anti$TB drugs

confusion "suspect drug$induced acute liver failure ifthere is 3aundice#

most anti$TBdrugs

Stop anti$TB drugs

'isual impairment "othercauses e%cluded#

ethambutol Stop ethambutol

Shoc&! purpura! acute renalfailure

rifampicin Stop rifampicin

decreased urine output Streptomycin Stop streptomycin

Minor ,ontinue anti-'( drugs chec drug doses

Anore%ia! nausea! abdominalpain

pyrainamide!rifampicin!isoniaid

give drugs with small meals or 3ustbefore bedtime! and advise patient toswallow pills slowly with small sips of

water( if symptoms persist or worsen! orthere is protracted vomiting or any sign

of bleeding! consider the side$effect to bema3or and refer to clinician urgently(

Moint pains pyrainamide Aspirin or non$steroidal anti$inammatory drug! or paracetamol

Burning! numbness or tinglingsensation in the hands or feet

isoniaid pyrido%ine *85;* mg daily "3#

drowsiness isoniaid reassurance( give drugs before bedtime

orange1red urine rifampicin reassurance( patients should be told when starting treatment that this mayhappen and is normal

flu syndrome "fever! chills!malaise! headache! bone pain#

intermittentdosing ofrifampicin

change from intermittent to dailyrifampicin administration "3#



)2


Of the 6rst-line anti-T% drugs+ isonia1id+ ,yra1inamide and rifam,icin can all causeli9er damage 5drug-induced he,atitis8" 0n addition+ rifam,icin can cause asym,tom-

atic Eaundice ithout e9idence of he,atitis" 0t is im,ortant to try to rule out other,ossible causes before deciding that the he,atitis is induced by the T% regimen"

The management of he,atitis induced by T% treatment de,ends on:

hether the ,atient is in the intensi9e or continuation ,hase of T% treatment< the se9erity of the li9er disease< the se9erity of the T%< and

the ca,acity of the health unit to manage the side-eects of T% treatment"

0f it is thought that the li9er disease is caused by the anti-T% drugs+ all drugs shouldbe sto,,ed" 0f the ,atient is se9erely ill ith T% and it is considered unsafe to sto, T%

treatment+ a non-he,atotoAic regimen consisting of stre,tomycin+ ethambutol and a[uoro@uinolone should be started"

0f T% treatment has been sto,,ed+ it is necessary to ait for li9er function tests tore9ert to normal and clinical sym,toms 5nausea+ abdominal ,ain8 to resol9e before

reintroducing the anti-T% drugs" 0f it is not ,ossible to ,erform li9er function tests+ itis ad9isable to ait an eAtra & ee=s after resolution of Eaundice and u,,er abdominal

tenderness before restarting T% treatment" 0f the signs and sym,toms do not resol9eand the li9er disease is se9ere+ the non-he,atotoAic regimen consisting of stre,tomy-

cin+ ethambutol and a [uoro@uinolone should be started 5or continued8 for a total of )4&! months 538"

Once drug-induced he,atitis has resol9ed+ the drugs are reintroduced one at a time"0f sym,toms recur or li9er function tests become abnormal as the drugs are reintro-duced+ the last drug added should be sto,,ed" 2ome ad9ise starting ith rifam,icin

because it is less li=ely than isonia1id or ,yra1inamide to cause he,atotoAicity andis the most eecti9e agent 53+ 48" *fter 3 days+ isonia1id may be reintroduced" 0n

,atients ho ha9e eA,erienced Eaundice but tolerate the reintroduction of rifam,icin

and isonia1id+ it is ad9isable to a9oid ,yra1inamide"*lternati9e regimens de,end on hich drug is im,licated as the cause of the he,a-

titis"

0f rifam,icin is im,licated+ a suggested regimen ithout rifam,icin is & months of isonia1id+ ethambutol and stre,tomycin folloed by )' months of isonia1id and

ethambutol"

0f isonia1id cannot be used+ 7( months of rifam,icin+ ,yra1inamide and ethambutolcan be considered"

0f ,yra1inamide is discontinued before the ,atient has com,leted the intensi9e ,hase+the total duration of isonia1id and rifam,icin thera,y may be eAtended to ( months

538"



)3

0f neither isonia1id nor rifam,icin can be used+ the non-he,atotoAic regimen con-sisting of stre,tomycin+ ethambutol and a [uoro@uinolone should be continued for a

total of )4&! months"

?eintroducing one drug at a time is the o,timal a,,roach+ es,ecially if the ,atientBshe,atitis as se9ere" .ational T% control ,rogrammes using FDC tablets should

therefore stoc= limited @uantities of single anti-T% drugs for use in such cases" Ho-e9er+ if the countryBs health units do not yet ha9e single anti-T% drugs+ clinical eA,e-rience in resource-limited settings has been successful ith the folloing a,,roach+hich de,ends on hether the he,atitis ith Eaundice occurred during the intensi9e

or the continuation ,hase"

X When he,atitis ith Eaundice occurs during the intensi9e ,haseof T% treatment

ith isonia1id+ rifam,icin+ ,yra1inamide and ethambutol: once he,atitis has re-sol9ed+ restart the same drugs JCPT re,lace ,yra1inamide ith stre,tomycinto com,lete the &-month course of initial thera,y+ folloed by rifam,icin and iso-

nia1id for the 7-month continuation ,hase"

X When he,atitis ith Eaundice occurs during the continuation ,hase:once he,atitishas resol9ed+ restart isonia1id and rifam,icin to com,lete the !-month continua-

tion ,hase of thera,y"

re!erences

0nternational 2tandards for Tuberculosis Care 502TC8)" + &nd ed" The Hague+ Tuberculo-sis Coalition for Technical *ssistance+ &''("?e9ised T% recording and re,orting forms and registers 9ersion &''7&" "Gene9a+ World

Health Organi1ation+ &''7 5WHO#HT$#T%#&''7"3< a9ailable at: htt,:##"ho"int#tb#dots#rYandYrYforms#en#indeA"html8" Toman N"" TomanBs tuberculosis" Case detection+ treatment+ and monitoring: @uestionsand ansers+ &nd ed" Gene9a+ World Health Organi1ation+ &''!"Williams G et al"!" %est ,ractice of the care for ,atients ith tuberculosis: a guide for loincome countries"Paris+ 0nternational Mnion *gainst Tuberculosis and Lung Disease+&''3"

Guidelines for the ,rogrammatic management of drug-resistant tuberculosis: emer-/"gency u,date &''4" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$# T%#&''4"!'&8"Williams G et al" Care during the intensi9e ,hase: ,romotion of adherence"7" 0nterna-tional ournal of Tuberculosis and Lung Disease+ &''4+ )&:7')7'/"

*merican Thoracic 2ociety+ CDC+ 0nfectious Diseases 2ociety of *merica" Treatment3"of tuberculosis"$orbidity and $ortality Wee=ly ?e,ort: ?ecommendations and ?e-,orts+ &''+/&5??-))8:)33"

2au==onen et al" *n oScial *T2 statement: he,atotoAicity of antituberculosis4" thera,y"*merican ournal of ?es,iratory and Critical Care $edicine+ &''7+ )3!:(/(/&"




)5

5

Co-management of Hi andacti9e T% disease


This cha,ter describes WHO recommendations for:

H0 testing and counselling of all ,atients =non or sus,ected to ha9e T%< H0 ,re9ention for T% ,atients< treatment of T% in ,eo,le li9ing ith H0<

,ro9iding co-trimoAa1ole ,re9enti9e thera,y to all H0-,ositi9e T% ,atients< hen to start antiretro9iral thera,y 5*?T8 and hat antiretro9iral agents to

use< drug susce,tibility testing and ,atient monitoring< ensuring com,rehensi9e H0 care and su,,ort ser9ices"

0m,lementing these recommendations re@uires collaboration beteen T% and H0#*0D2 ,rogrammes at all le9els 5)+ &8 and ill hel, to reduce the burden of H0 in

,eo,le diagnosed ith T%" 2imilarly+ collaboration is essential to reduce the burden

of T% in ,eo,le li9ing ith H0" 5While outside the sco,e of this cha,ter+ see: Three0Bs for reducing the burden of T% in ,ersons li9ing ith H0: 4ntensi6ed case-6nding50CF8+4sonia1id ,re9enti9e thera,y 50PT8 and T%4nfection control 50C8 for ,eo,leli9ing ith H0 58"8

Peo,le li9ing ith H0 are more li=ely to ,resent ith eAtra,ulmonary or s,utumsmear-negati9e T%+ es,ecially as immunosu,,ression ad9ances 5!+/8"This can result

in misdiagnosis or delays in diagnosis and+ in turn+ higher morbidity and mortality"0m,lementation of the WHO-recommended algorithms to diagnose ,ulmonary and

eAtra,ulmonary T% in H0-,re9alent settings is therefore crucial 578"5The treatmentof eAtra,ulmonary T% is discussed in Cha,ter 4"8

5. 2 'I( testing and counse##ing !or all *atients no/n or

sus*ected to have "

0rres,ecti9e of e,idemic setting+ WHO recommends H0 testing for ,atients of allages ho ,resent ith signs or sym,toms that suggest tuberculosis 538+ hether T% issus,ected or already con6rmed" 52ee also 2tandard )! of the 02TC 548"8T% is often the

6rst clinical indication that a ,erson has underlying H0 infection+ and T% ser9ices

can be an eAtremely im,ortant entry ,oint to H0 ,re9ention+ care and treatment 5)8"0n addition+ the H0 status of T% ,atients ma=es a dierence to their T% treatment"

52ee section /"!+ hich includes the ne recommendation for daily intensi9e-,hasedosing of anti-T% drugs for H0-,ositi9e T% ,atients"8



))


Detecting H0 infection in a T% ,atient is also critical for the T% ,atientBs householdmembers: H0-,ositi9e T% ,atients may ha9e household members ho are also li9ing

ith H0" Testing and counselling should be recommended for children and otherimmediate family members of all ,eo,le li9ing ith H0+ in cases here hori1on-

tal or 9ertical transmission may ha9e occurred" Within a family-centred a,,roachto H0 testing+ once a family member is identi6ed as ha9ing H0+ health or=ers

should encourage and acti9ely facilitate H0 testing for other family members" Thiscould be done+ here ,ossible and a,,ro,riate+ through cou,les or family testing

and counselling ser9ices 5(8") 2erodiscordant ,artnershi,s 5in hich one ,artner isH0-,ositi9e and the other is H0-negati9e8 ,ro9ide an im,ortant o,,ortunity for,re9ention of H0 transmission 5)'+))8"

Household contacts of an infectious T% case are a high ,riority for T% screening and

treatment+ es,ecially if they are li9ing ith H0 5&+)&+)8+ and those ho are foundto ha9e acti9e T% disease need ,rom,t treatment" *mong household contacts+ ,eo,le

li9ing ith H0 5and children+ regardless of their H0 status8 ho do not ha9e acti9e T% are candidates for isonia1id treatment to ,re9ent the de9elo,ment of acti9e T% 58"

52ee also 2tandards )7+ )4 and )( of the 02TC 548"8

WHO recommends ,ro9ider-initiatedQ testing+ hich means that the health care,ro9ider recommends H0 testing and counselling as a standard com,onent of care

538"For ,atients =non or sus,ected to ha9e T%+ ,ro9ider-initiated H0 testing can

be done at the same time the s,utum sam,les or chest radiogra,hs are obtained" Thisis more eScient+ and more li=ely to result in ,atients learning their H0 status+ than

referring them elsehere for H0 testing and counselling 5)&8"

*s in the case of client-initiated H0 testing+ informed consent+ counselling and con-6dentiality are essential" WHO recommends that ,ro9iders use o,t-outQ a,,roaches

538+ meaning that indi9iduals must s,eci6cally decline the H0 test after recei9ing,retest information if they do not ant the test to be ,erformed"

The ,ro9ision of H0 testing by the same health or=er ho ,ro9ides the T%

treatment 5or the ,ro9ision of H0 testing in the same facility8 has been shon tofacilitate H0 testing for T% ,atients 5)!+)/8"0f this is not ,ossible+ .TPs should ta=eres,onsibility for ensuring that any referred indi9idual actually goes for a test"

*n H0 testing ser9ice using ra,id assays oers se9eral ,rogrammatic ad9antages"?a,id assays are easy to use and can be carried out by any health care or=er ho

has recei9ed a,,ro,riate training" $ost ra,id H0 test =its can be stored at roomtem,erature 5u, to ' C8 and can be used for a single test ithout com,romising

the integrity of the remaining ,art of the test =it" $oreo9er+ the diagnostic ,erform-

ance of high-@uality ra,id assays is com,arable to that of traditional en1yme immu-noassays+ and the short turnaround time ensures that indi9iduals recei9e their test

results @uic=ly" These ra,id assays do not re@uire s,eciali1ed e@ui,ment and can be

) htt,:##"ho"int#hi9#,ub#,riorityYinter9entionsYeb",df



)+

5. Co&mana$EmEn o! 'I( and aCI(E" dISEaSE

,erformed outside the traditional laboratory setting 538" The 9isibility of the test 5tothe ,erson being tested8 and its s,eed increase con6dence in results and hel, to a9oid

clerical errors"

*s ith con9entional H0 assays+ a reacti9e result from the 6rst+ highly sensiti9e+ra,id assay re@uires con6rmation by a second+ more s,eci6c test+ ty,ically another

ra,id assay" 0f the second test yields non-reacti9e or indeterminate results+ a thirdtest may be ,erformed< if the result is reacti9e+ follo-u, H0 testing should be ,er-formed on a s,ecimen collected ! ee=s after the initial test" The follo-u, testingould rule out ,ossible serocon9ersion at the time of the initial test as the cause of

discre,ant testing results and ould re9eal most technical or clerical errors" The useof ra,id assay should be underta=en only ith functional @uality assurance in ,lace

and conducted according to the countryBs nationally 9alidated testing algorithm"

*,,ro,riate ,ost-test counselling should be ensured+ ith a strong focus on H0,re9ention< this ill also hel, ,re9ent the s,read of T%"

For more information+ see WHOBs2caling u, H0 testing and counselling ser9ices: atool=it for ,rogramme managers5&''/8+ hich is a9ailable online at: "ho"int#hi9#to,ics#9ct#tool=it#en#

5.3 'I( *revention in " *atients

.ational T% control ,rogrammes should de9elo, and im,lement com,rehensi9e

H0 ,re9ention strategies for their ,atients" *,,ro,riate ,re9ention messages andmethods should be ,ro9ided to ,atients ith con6rmed or sus,ected T%+ according

to their H0 status and local =noledge of the modes of transmission or assessmentof ris= 5)8"Harm-reduction measures for T% ,atients ho are inEecting drug users

should be ,ro9ided+ either by .TPs or through referral lin=ages to H0 ,rogrammes5&8"

5. % " treatment in *eo*#e #iving /ith 'I(

*mong treated T% ,atients+ death rates are higher in H0-,ositi9e than in H0-nega-ti9e ,atients" Case-fatality is higher in ,eo,le li9ing ith H0 ith smear-negati9e

,ulmonary and eAtra,ulmonary T%+ as these ,atients are generally more immuno-su,,ressed than those ith smear-,ositi9e T% 578"The case-fatality rate is reduced in,atients ho recei9e concurrent *?T 5see section /"7 belo8"

The 6rst ,riority for H0-,ositi9e T% ,atients is to initiate T% treatment+ folloed byco-trimoAa1ole and *?T 5)785see sections /"/ and /"7 belo8" For T% diagnosed in a,erson already ta=ing *?T+ see section /"("

.e T% ,atients li9ing ith H0 should be treated ith the regimens gi9en in)

Tables "& and "" Hoe9er+ the three times ee=ly intensi9e ,hase is no longer an

).e T% ,atients are those ho ha9e had no ,rior T% treatment or ho ha9e been recei9ing T% treat-ment for less than ) month"



),


o,tion" This ne recommendation is based on a systematic re9ie shoing that theincidence of rela,se and failure among H0-,ositi9e T% ,atients ho ere treatedith intermittent T% thera,y throughout treatment as & times higher than that

in ,atients ho recei9ed a daily intensi9e ,hase 5)38" 0n addition+ a study in 0ndiashoed that H0-,ositi9e ,atients ith ,ulmonary T% are at higher ris= of ac@uired

rifam,icin resistance+ hen failing a three times ee=ly short-course intermittentregimen 5)48"


T patients with nown positi!e H45 status and all T patients li!ing in H45,

pre!alent settings should recei!e daily T treatment at least during the inten,1

si!e phase

52trong#High grade of e9idence8L Recommendation (.2


patients





0n terms of duration of thera,y+ some eA,erts recommend ,rolonging T% treat-ment in ,ersons li9ing ith H0 in certain circumstances 5)(8" * systematic re9ie

found loer rela,se rates in ,eo,le li9ing ith H0 treated ith 4 or more monthsof rifam,icin-containing regimens com,ared ith the current recommendation of

7 months" Hoe9er+ the data @uality of the studies included in the re9ie as lo+and dierent durations of T% treatment for H0-,ositi9e and H0-negati9e indi-

9iduals ould be o,erationally diScult in resource-constrained and H0-,re9alentsettings 5)38"

L Recommendation (.(

4t is recommended that T patients who are li!ing with H45 should recei!e at

least the same duration o# T treatment as H45,negati!e T patients


H0-,ositi9e T% ,atients ho ha9e been ,re9iously treated for T% should recei9e thesame retreatment regimens as H0-negati9e T% ,atients 5see Table "/8"

)Countries+ subnational administrati9e units+ or selected facilities here the H0 ,re9alence amongadult ,regnant omen is U)V or among T% ,atients is U/V"



)9

?ifam,icin induces the acti9ity of he,atic en1ymes+ leading to sub-thera,eutic con-centrations of some antiretro9iral drugs" This is discussed in section /"7") belo"

5.5 Co&trimoxao#e *reventive thera*y0n all H0-,ositi9e T% ,atients+ co-trimoAa1ole ,re9enti9e thera,y should be initi-

ated as soon as ,ossible and gi9en throughout T% treatment" 52ee also 2tandard )/of the 02TC 548"8Co-trimoAa1ole ,re9enti9e thera,y substantially reduces mortalityin H0-,ositi9e T% ,atients 5)7+ &'8" The eAact mode of acti9ity is not clear but co-trimoAa1ole is =non to ,re9entPneumocystis Eiro9eciiand malaria and is li=ely toha9e an im,act on a range of bacterial infections in H0-,ositi9e T% ,atients"

* system for ,ro9iding co-trimoAa1ole ,re9enti9e thera,y to all ,eo,le li9ing ith

H0 ho ha9e acti9e T% should be established by T% and H0 ,rogrammes" Con-tinuation after T% treatment is com,leted should be considered in accordance ithnational guidelines"

For co-trimoAa1ole dosages+ contraindications+ and side-eects and their manage-ment+ see reference&'"

5.) antiretrovira# thera*y

*ntiretro9iral thera,y im,ro9es sur9i9al in H0-,ositi9e ,atients 5)78" 0n addition+

antiretro9iral thera,y reduces T% rates by u, to ('V at an indi9idual le9el+ by 7'Vat a ,o,ulation le9el and it reduces T% recurrence rates by /'V 5&)&&8"*?T shouldbe initiated forall,eo,le li9ing ith H0 ith acti9e T% disease irres,ecti9e of CD!

cell count" T% treatment should be started 6rst+ folloed by *?T as soon as ,ossibleand ithin the 6rst 4 ee=s of starting T% treatment 5&8"

*(7(- what ArT regimens to startN

2tandardi1ed+ sim,li6ed *?T regimens are used to su,,ort H0 treatment ,ro-grammes so they can reach as many ,eo,le li9ing ith H0 as ,ossible" For the most

u,-to-date WHO guidance on *?T regimens+ reference should be made to "ho"int#hi9#,ub#guidelines#en

WHO recommends that the 6rst-line *?T regimen contain to nucleoside re9ersetranscri,tase inhibitors 5.?T0s8 ,lus one non-nucleoside re9erse transcri,tase in-

hibitor 5..?T08" These are eScacious+ relati9ely less eA,ensi9e+ ha9e generic andFDC formulations+ do not re@uire a cold chain+ and ,reser9e a ,otent ne class of

agents 5,rotease inhibitors8 for second-line regimens" The ,referred .?T0 bac=boneis 1ido9udine 5*KT8 or tenofo9ir diso,roAil fumarate 5TDF8+ combined ith either

lami9udine 5TC8 or emtricitabine 5FTC8" For the ..?T0+ WHO recommends eitherefa9iren1 5F8 or ne9ira,ine 5.P8 5&8"

The recommended 6rst-line *?T regimens for T% ,atients are those that containefa9iren1 5F8+ since interactions ith anti-T% drugs are minimal" 0n se9eral cohort




+-


studies+ *?T ith standard-dose efa9iren1 and to nucleosides as ell toleratedand highly eScacious in achie9ing com,lete 9iral su,,ression among ,atients re-

cei9ing concomitant rifam,icin-based T% treatment 5&!8"

%ecause of concerns related to teratogenicity+ efa9iren1 should not be used in omenof childbearing ,otential ithout ade@uate contrace,tion+ nor should it be used foromen ho are in the 6rst trimester of ,regnancy" *lternati9es are also needed for

,atients ho are intolerant to efa9iren1 or are infected ith a strain of H0 that isresistant to ..?T0s" For those ho are unable to tolerate F or ho ha9e contrain-

dications to an F-based regimen+ *KT ;TC ; .P or TDF ;TC or FTC ; .Por a tri,le .?T0 regimen 5*KT;TC;*%C or *KT;TC;TDF8 is recommended< the

choice of regimen should be based on a9ailable regimens ithin countries" 0n coun-tries here rifam,icin is a9ailable+ the lead-in dose of ne9ira,ine is not necessary"

0n indi9iduals ho need T% treatment and ho re@uire an *?T regimen containinga boosted ,rotease inhibitor 5P08+ it is recommended to gi9e a rifabutin-based T%

treatment" 0f rifabutin is not a9ailable+ the use of rifam,icin and a boosted antiretro-9iral regimen containing lo,ina9ir or sa@uina9ir ith additional ritona9ir dosing is

recommended< this regimen should be closely monitored"

*(7(2 when to start ArTN

While the o,timal time to start *?T in relation to the start of T% thera,y is not

yet clear+ one randomi1ed controlled trial ,ro9ides some e9idence for early initia-tion of antiretro9iral thera,y in terms of reduced all-cause mortality+ im,ro9ed T%

outcomes and reduced incidence of immune reconstitution in[ammatory syndrome50?028 5&/8" The recommendations of WHO in &''( are that T% treatment should be

commenced 6rst and *?T subse@uently commenced+ as soon as ,ossible and ithinthe 6rst 4 ee=s of starting T% treatment" 0n this ra,idly e9ol9ing 6eld+ u,dated in-

formation and guidance on antiretro9iral thera,y is ,ro9ided by WHO 5see: htt,:##"ho"int#hi9#,ub guidelines#en8"

The rationale for starting *?T soon after T% diagnosis is that case-fatality amongH0-T% ,atients occurs mainly in the 6rst & months of T% treatment 5)78"Hoe9er+

early initiation of *?T 5ithin a fe ee=s of starting T% treatment8 means a largenumber of tablets to ingest+ hich may discourage treatment adherence< there may

also be com,lications ad9erse eects+ drugdrug interactions and 0?02"

$ild to moderate 0?02 is relati9ely common in ,atients ith T% started on *?T:it has been re,orted in u, to one-third of ,atients in some studies" Hoe9er+ it is

relati9ely rare in its se9ere forms 5&!+&78" The syndrome can ,resent as fe9er+ enlarg-

ing lym,h nodes+ orsening ,ulmonary in6ltrates+ or eAacerbation of in[ammatorychanges at other sites" 0t generally ,resents ithin months of the start of *?T andis more common hen CD! cell count is lo 5\/' cells#mm 8" $ost cases resol9e

ithout inter9ention and *?T can be safely continued 5&!8"



+1

0?02 is a diagnosis of eAclusion" Patients ith ad9anced *0D2 may sho clinical de-terioration for a number of other reasons" .e o,,ortunistic infections or ,re9iouslysubclinical infections may be unmas=ed folloing immune reconstitution and causeclinical orsening" 0?02 can also be confused ith T% treatment failure" 0n addition+

H0-,ositi9e T% ,atients may be demonstrating ,rogression of T% disease due to T%drug-resistance" 0?02 is not a reason to sitch ,atients to second-line *?T+ although

the *?T treatment regimen may need to be adEusted to ensure com,atibility ith the T% treatment 578"

5.+ drug susce*ti"i#ity testing

High mortality rates ha9e been re,orted among ,eo,le li9ing ith H0 ho ha9edrug resistant-T% 5&78+ and rates can eAceed ('V in ,atients coinfected ith eAten-

si9ely drug-resistant T% 5JD?-T%8 and H0 5&3+&48"Prom,t initiation of a,,ro,riate T% treatment 5and subse@uent initiation of *?T8 can reduce mortality among ,eo,le

li9ing ith H0 ho ha9e drug-resistant T% 5&48"

WHO recommends that .TPs underta=e D2T at the start of T% thera,y in all H0-,ositi9e T% ,atients+ to a9oid mortality due to unrecogni1ed drug-resistant T% 5&/8+

and strongly encourages the use of ra,id D2T in s,utum smear-,ositi9e ,ersonsli9ing ith H0 5&78"

0f the country is introducing D2T+ but does not yet ha9e the resources to test all H0-

,ositi9e T% ,atients+ initial .TP ,olicy should be to target D2T at the start of T%treatment for ,atients ith ,re9iously treated T%+ ho are 9ery li=ely to be multid-rug-resistant 5see section "4")8" This grou, includes ,atients hose ,rior T% treat-

ment has failed+ ho ha9e rela,sed or ho are returning from default" .TP managersmay also chose to target D2T for those H0-,ositi9e T% ,atients ith loer CD!

counts 5e"g" less than &'' cells#mm 8 gi9en their 9ery high ris= of death due to unrec-

ogni1ed drug-resistant T% 5&78"

5., atient monitoring during " treatment52ee also Cha,ter !"8

*d9erse drug eects are common in H0-,ositi9e T% ,atients+ and some toAicitiesare common to both *?T and T% drugs 5)78" O9erla,,ing toAicities beteen *?T+

T% thera,y and co-trimoAa1ole include rash 5and+ more rarely+ he,atic dysfunction8+and 9igilant monitoring of side-eects is therefore essential 5&'+&78"

5.9 Considerations /hen " is diagnosed in *eo*#e #iving /ith 'I( /ho

are a#ready receiving antiretrovira# thera*yWhen T% is diagnosed in ,atients already recei9ing *?T+ T% treatment should be

started immediately" There are to issues to consider in such cases: hether *?Tneeds to be modi6ed because of drugdrug interactions or to reduce the ,otential for




+2


o9erla,,ing toAicities+ and hether the ,resentation of acti9e T% in a ,atient on *?Tconstitutes *?T failure that re@uires a change in the *?T regimen" Diagnosis and

management of *?T failure are co9ered in another WHO document 5&(8"

5.1- 'I(&re#ated *revention= treatment= care and su**ort

The recommended ,ac=age of H0-related ,re9ention+ treatment+ care and su,,ortser9ices and su,,ort for ,eo,le li9ing ith H0 should be ,ro9ided either by T%

,rogrammes or by referral to H0#*0D2 ,rogrammes 5)&+)78"To im,ro9e treatmentsuccess+ the s,ecial needs of ,articular grou,s 5e"g" drug users+ ,risoners+ migrant

,o,ulations+ other marginali1ed grou,s8 should be assessed and addressed< theircare should be integrated ith other ser9ices"

* com,rehensi9e *0D2 care strategy includes clinical management 5,ro,hylaAis+early diagnosis+ treatment and follo-u, care for o,,ortunistic infections8+ nursing

care 5including hygiene ,romotion and nutritional su,,ort8+ ,alliati9e care+ homecare 5including education for care ,ro9iders and ,atientsB relati9es+ ,romoting uni-

9ersal ,recautions8+ counselling and social su,,ort 5)+ (8" This ,ac=age of care in-cludes a core set of eecti9e inter9entions+ listed belo+ that are sim,le and relati9elyineA,ensi9e+ can im,ro9e the @uality of life+ ,re9ent further transmission of H0

and+ in some cases+ delay ,rogression of H0 disease and ,re9ent mortality" 0n addi-tion to *?T+ these inter9entions ,romote health+ reduce the ris= of H0 transmission

to others+ and address diseases that most im,act the @uality and duration of life of adults and adolescents ith H0 58:

reducing the burden of T% 9ia intensi6ed T% case-6nding+ infection control+and isonia1id ,re9enti9e thera,y<

,sychosocial counselling and su,,ort< disclosure of H0 status+ ,artner noti6cation and testing and counselling< co-trimoAa1ole ,ro,hylaAis< ,re9enting fungal infections< ,re9enting seAually transmitted and other re,roducti9e tract infections< ,re9enting malaria<

,ro9iding selected 9accines 5he,atitis %+ ,neumococcal+ in[uen1a+ and yellofe9er8<

nutrition< family ,lanning< ,re9enting mother-to-child transmission of H0<

needle#syringe ,rogrammes and o,ioid substitution thera,y< and ater+sanitation and hygiene"



+3

re!erences

0nterim ,olicy on collaborati9e T%#H0 acti9ities)" " Gene9a+ World Health Organi1a-tion+ &''! 5WHO#HT$#T%#&''!"'+ WHO#HT$#H0#&''!")8"

0m,lementing the WHO 2to, T% strategy: a handboo= for national tuberculosis con-&" trol ,rogrammes" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$#T%#&''4"!')8"

WHO Three 0Bs $eeting: 0ntensi6ed case 6nding 50CF8+ 0sonia1id ,re9enti9e thera,y"50PT8 and T% 0nfection control 50C8 for ,eo,le li9ing ith H0"?e,ort of a Eoint World

Health Organi1ation H0#*0D2 and T% de,artment meeting" Gene9a+ World HealthOrgani1ation+ &''4 5a9ailable at: htt,:##"ho"int#hi9#,ub#meetingre,orts#WHOY0sYmeetingYre,ort",df8" T%#H0: a clinical manual!" + &nd ed" Gene9a+ World Health Organi1ation+ &''!5WHO#HT$#T%#&''!"&(8"

Getahun H et al" Diagnosis of smear-negati9e ,ulmonary tuberculosis in ,eo,le ith/"H0 infection or *0D2 in resource-constrained settings: informing urgent ,olicy

changes"Lancet+ &''3+ 7(:&'!&&'!("0m,ro9ing the diagnosis and treatment of smear-negati9e ,ulmonary and eAtra,ulmo-7"nary tuberculosis among adults and adolescents: recommendations for H0-,re9alent

and resource-constrained settings"Gene9a+ World Health Organi1ation+ &''3 5WHO#HT$#T%#&''3"3(< WHO#H0#&''3")8"WHO+ M.*0D2"3" Guidance on ,ro9ider-initiated H0 testing and counselling inhealth facilities" Gene9a+ World Health Organi1ation+ &''3"

0nternational 2tandards for Tuberculosis Care 502TC84" + &nd ed" The Hague+ Tuberculo-sis Coalition for Technical *ssistance+ &''(" Toards uni9ersal access: ,riority inter9entions for H0(" " Gene9a+ World Health Or-gani1ation+ &''4"Dun=le NL et al" .e heteroseAually transmitted H0 infections in married or co-)'"

habiting cou,les in urban Kambia and ?anda: an analysis of sur9ey and clinicaldata"Lancet+ &''4+ 3):&)4&)()"

O,ening u, the H0#*0D2 e,idemic: guidance on encouraging bene6cial disclosure+))"ethical ,artner counselling ^ a,,ro,riate use of H0 case-re,orting" Gene9a+ Mnited

.ations oint Programme on H0#*0D2+ &''' 5a9ailable at: htt,:##"ho"int#ethics#to,ics#o,eningYu,YethicsYandYdisclosureYenY&'''",df 8"

Tuberculosis care ith T%-H0 co-management: integrated management of adoles-)&"cent and adult illness 50$*08" Gene9a+ World Health Organi1ation+ &''3"

Ha9lir D et al" O,,ortunities and challenges for H0 care in o9erla,,ing H0 and)" T% e,idemics" ournal of the *merican $edical *ssociation+ &''4+ '':!&!'"

.unn P+ De Coc= N" $easuring ,rogress toards integrated T%-H0 treatment and)!"care ser9ices: are countries doing hat needs to be done0nternational ournal of Tuberculosis and Lung Disease+ &''4+ )&5 2u,,l" )8:)"Gasana $ et al" 0ntegrating tuberculosis and H0 care in rural ?anda")/" 0nterna-

tional ournal of Tuberculosis and Lung Disease+ &''4+ )&5 2u,,l" )8:(!"Harries *D+ Kachariah ?+ Lan 2D" Pro9iding H0 care for co-infected tuberculosis)7",atients: a ,ers,ecti9e from sub-2aharan *frica"0nternational ournal of Tuberculo-sis and Lung Disease+ &''(+ ):7)7"




+%


Nhan F* et al" Treatment of acti9e tuberculosis in H0 co-infected ,atients: a sys-)3"tematic re9ie and meta-analysis"Clinical 0nfectious Diseases+ &')' 5in ,ress8"2aminathan 2 et al")4" *c@uired rifam,icin resistance in H0-infected and uninfected

,atients ith tuberculosis treated ith a thrice-ee=ly short-course regimen" Poster

,resented at Conference on ?etro9iruses and O,,ortunistic 0nfections 5C?O08+$ontreal+ &''( 5a9ailable at: htt,:##"retroconference"org#&''(#*bstracts#/&!"

htm8"*merican Thoracic 2ociety+ CDC+ 0nfectious Diseases 2ociety of *merica" Treat-)("

ment of tuberculosis"$orbidity and $ortality Wee=ly ?e,ort: ?ecommendations and?e,orts+ &''+ /&5??-))8:)33"

Guidelines on co-trimoAa1ole ,ro,hylaAis for H0-related infections among children+&'"adolescents and adults in resource-limited settings: recommendations for a ,ublic

health a,,roach" Gene9a+ World Health Organi1ation+ &''7"

Lan 2D+ Churchyard G" ,idemiology of H0-associated tuberculosis"&)" CurrentO,inion in H0 and *0D2+ &''(+ !:&/"Golub et al" Long-term eecti9eness of diagnosing and treating latent tuberculo-&&"

sis infection in a cohort of H0-infected and at ris= inEection drug users" ournal of *c@uired 0mmune De6ciency 2yndromes+ &''4+ !(5/8:/&/3"

?a,id ad9ice for antiretro9iral thera,y for H0 infection in adults and adolescents&" "Gene9a+ World Health Organi1ation+ &''( 5a9ailable at htt,:##"ho"int#hi9#,ub#

ar9#ra,idYad9iceYart",df8"$anaging drug interactions in the treatment of H0-related tuberculosis&!" "*tlanta+ G*+

Centers for Disease Control and Pre9ention+ &''3 5a9ailable at: "cdc"go9#tb#,ub-lications#guidelines#T%YH0YDrugs#PDF#tbhi9",df8"

Narim 2* et al" 0nitiating *?T during T% treatment signi6cantly increases sur9i9al:&/"results of a randomi1ed controlled clinical trial in T%#H0-co-infected ,atients in

2outh *frica" Pa,er ,resented at Conference on ?etro9iruses and O,,ortunistic 0n-fections 5C?O08+ $ontreal+ &''( 5a9ailable at: htt,:##"retroconference"org#&''(#

*bstracts#!&//"htm8"Guidelines for the ,rogrammatic management of drug-resistant tuberculosis: emer-&7"

gency u,date &''4" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$#T%#&''4"!'&8"

Gandhi .? et al" Atensi9ely drug-resistant tuberculosis as a cause of death in ,a-&3"tients co-infected ith tuberculosis and H0 in a rural area of 2outh *frica"Lancet+&''7+ 74:)/3/)/4'"

Wells CD et al" H0 infection and multidrug-resistant tuberculosis: the ,erfect&4"storm" ournal of 0nfectious Diseases+ &''3+ )(752u,,l" )8:2472)'3"

ssential ,re9ention and care inter9entions for adults and adolescents li9ing ith H0&("in resource-limited settings" Gene9a+ World Health Organi1ation+ &''4"



+5

)

su,er9ision and ,atient su,,ort

).1 Cha*ter o"4ectives


the role of the ,atient+ the T% ,rogramme+ other ,ro9iders+ and the commu-nity in the cure of T%<

treatment su,er9ision and directly obser9ed thera,y<

,atient-centred care< measures to ,re9ent interru,tion of treatment"

*dherence to T% treatment is crucial to achie9ing cure hile a9oiding the emer-gence of drug resistance" ?egular and com,lete medication inta=e gi9es indi9idual

T% ,atients the best chance of cure and also ,rotects the community from the s,readof T%" The emergence and s,read of $D?- and JD?-T% further reinforces the ab-

solute necessity of hel,ing a T% ,atient to not miss any drug doses" 0n the 2to, T%2trategy+ su,er9ision and ,atient su,,ort remain the cornerstone of DOT2 and hel,

,rogrammes to achie9e the treatment success target of 4/V 5)8"

). 2 ro#es o! the *atient= " *rogramme sta!!= the community

and other *roviders

Cure can be achie9ed only if the ,atient and the health ser9ice sta or= together 5&8"Other health care ,ro9iders and the community also ha9e im,ortant roles to ,lay"

7(2(- patient as partner

*ccording to the PatientsB Charter for T% Care+ ,atients are not ,assi9e reci,ientsof ser9ices but acti9e ,artners 58" They ha9e the right to care+ dignity+ information+,ri9acy+ food su,,lements and#or other ty,es of su,,ort and incenti9es+ if needed"

They also ha9e the right to ,artici,ate in T% ,rogramme de9elo,ment+ im,lemen-tation and e9aluation" Patients ha9e the res,onsibility of sharing information ith

the health ,ro9ider+ folloing treatment+ contributing to community health+ andshoing solidarity by ,assing eA,ertise gained during treatment to others in the

community" %ecause of their 6rst-hand T% eA,erience+ their in9ol9ement in stigma-reduction acti9ities in the community and su,,orting treatment com,letion of other

,atients can be highly eecti9e"



+)


7(2(2 role of the nTp and its staff

%ecause T% is a ,ublic health ,roblem and its transmission ,oses a ris= to the com-munity+ ensuring regular inta=e of all the drugs by the ,atient is a res,onsibility of

the health sta and of the .TP" To facilitate ,atient adherence+ .TPs need to estab-lish and maintain systems that maAimi1e ,atient access to care+ and train and su,er-9ise health or=ers to ,ro9ide ,atient-centred care" Factors such as the ty,e of drug

regimen 5daily or intermittent8+ the ty,e of drug formulation 56Aed-dose combina-tions or se,arate drugs8 as ell as the circumstances and characteristics of the ,atient

should be considered in organi1ing ,atient su,er9ision 5see section 7"!8"

To su,,ort ,atient adherence+ it is critical for the .TP to im,lement to additionalcom,onents of the 2to, T% 2trategy: engaging other care ,ro9iders and in9ol9ing

communities 5)8"

7(2() engaging providers outside the TB programme

WHO has de9elo,ed guidance on engaging all health care ,ro9iders to ta=e on T%tas=s according to their ca,acity 5!8" For eAam,le+ ,ublic and ,ri9ate ,ractitioners

can successfully ,ro9ide DOT2 in collaboration ith the .TP" *t a minimum+ any,ractitioner treating a ,atient for T% must be ca,able of 5/8:

discussing the condition and the treatment being gi9en to the ,atient<

recogni1ing and managing ad9erse eects of medications+ and ma=ing refer-rals if necessary< assessing the ,atientBs adherence to the regimen and addressing ,oor adher-

ence hen it occurs 502TC 2tandard 3 5788< com,leting the a,,ro,riate documentation< collaborating ith the local ,ublic health ser9ices< ensuring that the ,atient acce,ts the ,ro,osed care"

7(2(4 community involvement

*nother com,onent of the 2to, T% 2trategy is to em,oer communities 5)8" Com-munity in9ol9ement refers to ,artnershi, and shared res,onsibility ith health ser-

9ices 538"2ocial mobili1ation can create demand for @uality-assured T% ser9ices andhel, the community to a9ail itself of these ser9ices"

0n community-based care+ a T% treatment su,,orter shares ith the T% ,atient re-s,onsibility for the successful com,letion of treatment< he or she ,ro9ides thera,y

under su,er9ision as ell as social and ,sychological su,,ort 548"Community-basedcare can hel, to eA,and access to care but re@uires a strong re,orting system+ access

to laboratory facilities+ and a secure drug su,,ly" Treatment su,,orters need regularcontact ith .TP sta to ensure that moti9ation and successful outcomes are main-

tained" Community based T% care is a sign of commitment by the .TP to ,artner-shi, ith the community"



++

). S uEr(ISIon and aIEnSuor

).3 Su*ervised treatment

2u,er9ised treatment refers to hel,ing ,atients to ta=e their T% medications regu-larly and to com,lete T% treatment" 0t is also meant to ensure that the ,ro9iders gi9e

,ro,er care and are able to detect treatment interru,tion" One eAam,le of treatmentsu,er9ision is recording each dose of anti-T% drugs on the ,atientBs treatment card"

Directly obser9ed thera,y 5DOT8+ a recommended method of su,er9ision+ shouldbe seen as a ,art of a su,,ort ,ac=age that addresses ,atientsB needs" This ,ac=age

should hel, to ensure that DOT is sensiti9e to+ and su,,orti9e of+ the ,atientBs needs"* treatment su,,orter obser9ing inta=e of e9ery dose ensures that a T% ,atient ta=es

the right anti-T% drugs+ in the right doses+ at the right inter9als" ?egular su,er9isionand su,,ort hel, to maintain fre@uent communication beteen the ,atient and a

health or=er or treatment obser9er< this ,ro9ides more o,,ortunities for T% educa-tion+ identi6cation and resolution of obstacles to treatment+ and early identi6cationof non-adherence alloing inter9entions to return the ,atient to the ,rescribed

treatment" ?egular su,er9ision also allos the ,rom,t detection and management of ad9erse drug reactions and clinical orsening of T%"

*s a method of su,er9ision recommended by WHO+ DOT has been the subEect of much debate 5(8" * systematic re9ie of siA controlled trials com,aring DOT ithself-administered thera,y concluded that DOT did not im,ro9e outcomes 5)'8"Ho-

e9er+ this re9ie too= no account of the ,atient su,,ort ser9ices ,ro9ided in addi-

tion to the routine su,er9ised salloingQ or of the im,act of DOT in ,re9entingthe emergence of drug resistance 5))8" Other re9ies found DOT to be associatedith high cure and treatment com,letion rates 5(+)&8"The highest success rates ere

achie9ed in ,rogrammes that used DOT in the conteAt of a full su,,ort ,ac=age+ ithcom,onents such as incenti9es and enablers 5discussed in section 7"! belo8 5)+)!8"

Direct obser9ation of each dose of drugs is most critical in the intensi9e ,hase+ henintermittent dosing is used during either ,hase+ and in the treatment of+ for eAam,le+

,sychologically handica,,ed ,atients+ ,rison inmates+ or ,atients recei9ing second-

line anti-T% drugs" 2u,er9ised treatment should be carried out in a conteAt-s,eci6cand ,atient-friendly manner" There must be [eAibility in ho DOT is a,,lied+ ith

ada,tation to dierent settings that are con9enient to the ,atient" The hole ,ur,oseof treatment obser9ation ould be defeated if it ere to limit access to care+ turn ,a-

tients aay from treatment+ or add to their hardshi,s"

De,ending on the local conditions+ su,er9ision may be underta=en at a health facil-ity+ in the or=,lace+ in the community or at home" * treatment su,,orter must be

identi6ed for each T% ,atient< he or she should be a ,erson acce,table to+ and chosen

ith+ the ,atient" For T% ,atients ho li9e close to a health facility+ the treatmentsu,,orter ill be one of the sta in the health facility+ and this is the ideal choice if con9enient to the ,atient" Collaboration ith other ,rogrammes allos the identi6-

cation of sta from these ,rogrammes ho may obser9e T% treatment"



+,


For T% ,atients ho li9e far aay from a health facility the treatment obser9er ill bea community health or=er or a trained and su,er9ised local community member"

With suitable training and monitoring+ H0#*0D2 community care ,ro9iders canobser9e T% treatment" Cured T% ,atients may be successful DOT ,ro9iders+ as can

traditional healers+ friends+ co-or=ers+ family members+ neighbours+ religious lead-ers+ etc" 5)/8< in fact+ any illing ,erson ho is acce,table to the ,atient and anser-able to the health system can be a treatment su,,orter"

The .TP is res,onsible for training and monitoring the non-medical treatmentobser9ers" There must be a clearly de6ned line of accountability from .TP sta to

general health ser9ices sta and the treatment su,,orter" 0t is im,ortant to ensurecon6dentiality and the acce,tability of su,er9ised treatment to the ,atient" The drugs

should remain ith the treatment su,,orter and be gi9en to the ,atient only at the

time of ingestion"

There may be an incenti9e for community members to become obser9ers of T% treat-ment" 0ncenti9es for 9olunteers and ,atients may be considered+ bearing in mind the

ad9antages and disad9antages of incenti9e schemes 5)78"

Detailed instructions for informing the ,atient and family about T% and its treat-ment and for arranging su,er9ised treatment 5including identifying and ,re,aring a

community T% treatment su,,orter8 are contained in WHOBs training modules forhealth facility sta 5)38"

). % using a *atient&centred a**roach to care and treatment de#ivery

$any .TPs no ha9e considerable eA,erience in im,lementing adherence ,romo-tion strategies that or= and in tailoring DOT to a gi9en conteAt" Locally a,,ro,ri-

ate measures should be ta=en to identify and address ,hysical+ 6nancial+ social andcultural 5as ell as health system8 obstacles to accessing T% treatment ser9ices 5)48"

Particular attention should be ,aid to the ,oorest and most 9ulnerable grou,s" *lsouseful are eA,licit eorts to address gender issues+ im,ro9e sta attitudes+ and en-

hance communication" 0t is essential that these a,,roaches be based on ethical ,rin-ci,les regarding the needs+ rights+ ca,abilities and res,onsibilities of ,atients+ their

families and their communities" 52ee also 2tandards 3+ ( and )3 of the 02TC 578"8

For any chosen method of su,er9ision and administration of treatment+ a ,rogrammemust sho high s,utum smear con9ersion and cure rates+ under routine conditions+in both rural and urban areas" 0f e9aluation shos subo,timal results+ the method of su,er9ision and administration of the regimen should be altered and tested in dem-

onstration and training districts"

0n addition to su,er9ised treatment 5or DOT8+ measures to su,,ort ,atient adher-ence to regular and com,lete treatment include:



+9

X* regular su,,ly of drugs ,ro9ided free of charge<

allocated in ,atient =its+ to ensure that drugs for the full course of treatmentare reser9ed for the ,atient at the outset of treatment<

in 6Aed-dose combinations and blister ,ac=s+ to hel, reduce medication erroras ell as facilitating adherence"

X*ccessible+ high-@ualiXy+ conXinuous ambulaXory T% care 5if XreaXmenX is healXhfacility-based8

eA,anding treatment outlets in the ,oorest rural and urban settings and in-9ol9ing ,ro9iders ho ,ractise close to here ,atients li9e 5thus reducing tra9-

el costs and loss of time and ages8< con9enient clinic hours ith minimal aiting times<

ade@uate numbers of moti9ated health or=ers ith managerial su,,ort< [eAibility to ma=e a,,ro,riate arrangements for transfer to another facility

5)(8< ability to ma=e arrangements u,on release from ,rison or hos,ital to continue

care on an ambulatory basis in the ,atientBs community"

XPosiXi9e acXion Xo remo9e barriers Xo XreaXmenX and care ensuring that all ser9ices ,ro9ided are aordable 5if not free8+ and eliminating

cost of care<

a,,ro,riate ,atient education+ including information regarding the regimen+duration and ,ossible treatment outcomes+ ,ro9ided re,eatedly by ell-trained

and considerate sta< ,rom,t detection and management of ad9erse drug reactions<

a9ailability of other forms of treatment su,,ort 5such as community+ or=-,lace+ or other8 are a9ailable hen facility-based treatment ,oses an obstacle

for the ,atient< ,ro9ision or 6nancing of trans,ortation+ and other treatment enablers that can

com,ensate ,atients for the indirect costs of care<

,ro9ision of incenti9es such as food or hygienic ,ac=ages for ,atients and theirfamilies+ if a,,ro,riate for the conteAt and for the ,atient<

,atient and ,eer su,,ort grou,s+ hich may hel, also reduce stigma< referrals for ,sychological+ social and legal su,,ort and other ser9ices includ-

ing substance abuse treatment< Eoint 5integrated8 su,,ort for T% ,atients ithaddicti9e beha9iours<

ready a9ailability of concomitant H0 treatment"

X*9ailabiliXy of hos,iXali1aXion

Hos,itali1ation is essential for se9erely ill ,atients and for those ith com,licationsor associated conditions re@uiring closer clinical monitoring" 0t might also be an

alternati9e+ es,ecially during the initial ,hase of treatment+ for a small number of




,-


,atients for hom other means of ensuring treatment adherence and su,,ort arenot a9ailable" Hoe9er+ hos,itali1ation ,er se does not ensure regular drug inta=e

or com,letion of the treatment" Patient-centred su,,ort and su,er9ision are Eust asim,ortant to success in an in,atient setting as in the community"

).5 revention o! treatment interru*tion

Globally+ /V of ne smear-,ositi9e cases treated under DOT2 in &''7 defaulted+but this ranges from \)V to )V in the orldBs && high-burden countries" Defaultincludes ,atients ho ha9e interru,ted treatment but also ,atients ho ha9e died

or transferred out and hose outcomes are un=non to the .TP treatment sta" The true status of the defaulting ,atientQ must be ascertained: if defaulting is due

to treatment interru,tion+ and if it could be ,re9ented+ additional countries ould

be able to achie9e the global T% control target of 4/V treatment success" Treatmentinterru,tion can be ,re9ented or limited so that a ,atient does not default entirely

from thera,y 5&'8"Promoting adherence through a ,atient-centred a,,roach is ,rob-ably more eecti9e in ,re9enting treatment interru,tion than de9oting resources to

tracing ,atients ho default"

*mong the maEor factors that in[uence treatment interru,tion are comorbid condi-tions such as substance abuse or mental illness+ access to treatment 5distance+ cost

of trans,ort8 5&)8+ time and ages lost+ @uality and s,eed of drug deli9ery+ eAtent of

=noledge about T% and the need to com,lete treatment+ and [eAibility for transferto another facility"

*s described in section 7"!+ su,er9ised treatment can hel, ,re9ent interru,tions"When ,atients self-administer treatment+ they often ta=e drugs irregularly+ and trac-

ing is diScult and often un,roducti9e< there is also a much longer delay beteeninterru,tion of treatment and action by the health system"

Whene9er the ,atient 9isits the health facility+ the need for regular and com,leteinta=e of treatment should be reinforced and any ,roblems that may cause inter-

ru,tion should be identi6ed" *t registration+ suScient time should be set aside formeeting ith the ,atient 5and ,referably also the ,atientBs family members or a desig-

nated treatment su,,orter8" This initial meeting ,ro9ides an im,ortant o,,ortunityto inform the ,atient about the duration of treatment" During the meeting+ it is 9ital

to record the ,atientBs address and other rele9ant addresses 5e"g" ,artner or s,ouse+,arents+ ,lace of or= or study+ or ,ri9ate doctor ho may be consulted8 as ell as

eA,lain the need to consult ahead of time in case of a change of address" This maAi-mi1es the li=elihood of locating ,atients ho interru,t treatment" ?ecording mobile

tele,hone numbers for the ,atient and family has ,ro9ed 9aluable in many settings"

Where resources ,ermit+ it is hel,ful for a health sta member to accom,any the ,a-tient to his or her residence" This allos 9eri6cation of the ,atientBs eAact address and

,ro9ides an o,,ortunity to arrange for screening of household contacts+ es,ecially



,1

children under / years of age and those of any age ho may ha9e T% sym,toms or beli9ing ith H0"

0n the meeting ith the ,atient at the end of the initial ,hase of treatment+ the health

or=er should reassess his or her needs and en@uire about ,lans 5or=+ family+ mo9-ing to another location8 that may aect the continuation ,hase of treatment 5)(8"*ny

changes in the regimen should be discussed and all concerns should be addressed"

re!erences

The 2to, T% 2trategy: building on and enhancing DOT2 to meet the T%-related $illen-)"nium De9elo,ment Goals"Gene9a+ World Health Organi1ation+ &''7 5WHO#HT$# T%#&''7"748"Williams G et al" Care during the intensi9e ,hase: ,romotion of adherence"&" 0nterna-

tional ournal of Tuberculosis and Lung Disease+ &''4+ )&:7')7'/"PatientsB charter for tuberculosis care: ,atientsB rights and res,onsibilities" " Gene9a+World Care Council+ &''7"

ngaging all health care ,ro9iders in T% control: guidance on im,lementing ,ublic-!",ri9ate miA a,,roaches" Gene9a+ World Health Organi1ation+ &''7 5WHO#HT$# T%#&''7"7'8"

T% guidelines for nurses in the care and control of tuberculosis and multi-drug resis-/"tant tuberculosis" Gene9a+ 0nternational Council of .urses+ &''4"0nternational 2tandards for Tuberculosis Care 502TC87" + &nd ed" The Hague+ Tuberculo-

sis Coalition for Technical *ssistance+ &''("Community in9ol9ement in tuberculosis care and ,re9ention" Toards ,artnershi,s3"for health: guiding ,rinci,les and recommendations based on a WHO re9ie"Gene9a+World Health Organi1ation+ &''4 5WHO#HT$#T%#&''4"(38"?a9iglione $+ ed"4" ?eichman and Hersh6eldBs tuberculosis: a com,rehensi9e+ interna-tional a,,roach+ rd ed" .e or=+ 0nforma Healthcare+ &''7"

Frieden T?+ 2barbaro *" Promoting adherence to treatment for tuberculosis: the("im,ortance of direct obser9ation"%ulletin of the World Health Organi1ation+ &''3+4/:!'3!'("olmin= + Garner P" Directly obser9ed thera,y for treating tuberculosis")'" CochraneDatabase of 2ystematic ?e9ies+ &''3+ 5!85!8:CD''!"

?usen 0D et al" Cochrane systematic re9ie of directly obser9ed thera,y for treating))"tuberculosis: good analysis of the rong outcome"0nternational ournal of Tubercu-losis and Lung Disease+ &''3+ )):)&')&)"Ho,eell PC et al" 0nternational standards for tuberculosis care")&" Lancet 0nfectiousDiseases+ &''7+ 7:3)'3&/"

2uare1 PG et al" The dynamics of tuberculosis in res,onse to )' years of intensi9e)"control eort in Peru" ournal of 0nfectious Diseases+ &'')+ )4!:!3!34"

Chaul= CP+ Na1andEian *" Directly obser9ed thera,y for treatment com,letion)!"

of ,ulmonary tuberculosis: consensus statement of the ,ublic health tuberculosisguidelines ,anel" ournal of the *merican $edical *ssociation+ )((4+ &3(:(!(!4"

Pungrassami P et al" Practice of directly obser9ed treatment 5DOT8 for tuberculosis)/"in southern Thailand: com,arison beteen dierent ty,es of DOT obser9ers"0nter-national ournal of Tuberculosis and Lung Disease+ &''&+ 7:4((/"




,2


%eith *+ ichler ?+ Weil D" Performance-based incenti9es for health: a ay to im-)7",ro9e tuberculosis detection and treatment com,letion Washington+ DC+ Center for

Global De9elo,ment+ &''3 5CGD Wor=ing Pa,er+ no" )&&8"$anagement of tuberculosis: training for health facility sta )3" " Gene9a+ World Health

Organi1ation+ &'' 5WHO#CD2#T%#&''")!8"$unro 2* et al" Patient adherence to tuberculosis treatment: a systematic re9ie of )4"

@ualitati9e research"PLo2 $edicine+ &''3+ !:e&4"Williams G et al" Care during the continuation ,hase")(" 0nternational ournal of Tuber-culosis and Lung Disease+ &''4+ &:3)3/"Williams G et al"&'" %est ,ractice of the care for ,atients ith tuberculosis: a guide for loincome countries"Paris+ 0nternational Mnion *gainst Tuberculosis and Lung Disease+&''3"

2hargie %+ LindtEorn %" Determinants of treatment adherence among smear-,ositi9e&)"

,ulmonary tuberculosis ,atients in southern thio,ia"PLo2 $edicine+ &''3+ !:e3"



,3

+

Treatment of drug-resistanttuberculosis

+.1 Cha*ter o"4ectives


the Green Light Committee one of the sources of su,,ort to countries estab-lishing a drug-resistant T% com,onent and integrating it into their .TP<

grou,s of drugs used to treat $D?-T%+ and the ,rinci,les for constructing an

$D?-T% regimen< ,rogrammatic strategies for $D?-T% treatment ho to select the standard$D?-T% regimen 5and considerations for an indi9iduali1ed a,,roach once

D2T results are a9ailable8< ho to monitor $D?-T% ,atients+ determine hen to sto, the inEectable agent+

and decide hen treatment is com,leted< ho to treat T% ith resistance ,atterns other than $D?< recording and re,orting of drug-resistant T% cases"

This cha,ter highlights =ey conce,ts for treating drug-resistant T% ,re9enting thede9elo,ment of drug resistance+ and detecting it ,rom,tly hen it does occur+ arediscussed in Cha,ters to 7"

This cha,ter is intended to ser9e as a brief o9er9ie" $anagers of .TPs ho are es-tablishing a drug-resistant com,onent and integrating it into their ,rogrammes are

strongly urged to see= eA,ert consultation 5see section 3"& belo8 and to re9ie the&''4 or subse@uent editions of the WHOGuidelines for the ,rogrammatic manage-ment of drug resistant T%5)8") 52ee also 2tandard )& of the 02TC 5&8"8

+.2 $reen #ight Committee Initiative

0n designing the countryBs $D?-T% treatment com,onent and integrating it into thenational ,rogramme+ .TP managers are strongly encouraged to ma=e full use of theGreen Light Committee 5GLC< "ho"int#tb#challenges#mdr#greenlightcommittee8"

The GLC is a subgrou, of the $D?-T% Wor=ing Grou, of the 2to, T% Partnershi,+and an ad9isory body of WHO that ,romotes access to 5and monitors the use of8

@uality-assured+ life-sa9ing $D?-T% treatment"

) That ,ublication also ,ro9ides in-de,th guidance on the many facets of $D?-T% management+ in-cluding management of side-eects and indications for surgery"



,%


Through the GLC 0nitiati9e+ .TPs ha9e access to:

eA,ertise in ,rogrammatic management of drug-resistant T% based on besta9ailable e9idence and collecti9e eA,erience<

high-@uality drugs to treat drug-resistant T% at concessional ,rices< su,,ort through a ide netor= of technical ,artners<

,eer su,,ort and =noledge-sharing ith other GLC-a,,ro9ed ,rogrammes< inde,endent eAternal monitoring and e9aluation"

+.3 $rou*s o! drugs to treat mdr&"

For $D? treatment+ anti-T% drugs are grou,ed according to eScacy+ eA,erience of use and drug class 5Table 3")8" *ll the 6rst-line anti-T% drugs are in Grou, )+ eAce,t

stre,tomycin+ hich is classi6ed ith the other inEectable agents in Grou, &" *ll thedrugs in Grou,s &/ 5eAce,t stre,tomycin8 are second-line+ or reser9e+ drugs" Thefeatures of the drugs ithin each grou,+ including cross-resistance+ are discussed in

more detail belo" Cross-resistance means that resistance mutations 5in$" tuberculo-sisbacteria8 to one anti-T% drug may confer resistance to some or all of the membersof the drug family and+ less commonly+ to members of dierent drug families 5)8"

@roup 1.Grou, ) drugs are the most ,otent and best tolerated" 0f there is good labo-ratory e9idence and clinical history that suggests that a drug from this grou, is ef-

fecti9e+ it should be used" 0f a Grou, ) drug as used in a ,re9ious regimen

thatfailed+ its eScacy should be @uestioned e9en if the D2T result suggests susce,tibility" The neer rifamycins+ such as rifabutin+ ha9e 9ery high rates of cross-resistance to

rifam,icin"

@roup 2.*ll ,atients should recei9e a Grou, & inEectable agent if susce,tibility isdocumented or sus,ected" *mong aminoglycosides+ =anamycin or ami=acin is the

6rst choice of an inEectable agent+ gi9en the high rates of stre,tomycin resistance indrug-resistant T%" 0n addition+ both these agents are ineA,ensi9e+ cause less otoA-

icity than stre,tomycin+ and ha9e been used eAtensi9ely for the treatment of drug-

resistant T%" *mi=acin and =anamycin are considered to be 9ery similar and ha9e ahigh fre@uency of cross-resistance" 0f an isolate is resistant to both stre,tomycin and=anamycin+ or if D?2 data sho high rates of resistance to ami=acin and =anamycin+

ca,reomycin 5a ,oly,e,tide8 should be used"

@roup 3.*ll ,atients should recei9e a Grou, medication if the$" tuberculosisstrain is susce,tible or if the agent is thought to ha9e eScacy" One of the higher gen-

eration [uoro@uinolones+ such as le9o[oAacin or moAi[oAacin+ is the [uoro@uinolo-ne of choice" Ci,ro[oAacin is no longer recommended to treat drug-susce,tible or

drug-resistant T%"@roup (.thionamide 5or ,rotionamide8 is often added to the treatment regimenbecause of its lo cost" 0f cost is not a constraint+,-aminosalicylic acid 5P*28 may be

added 6rst+ gi9en that the enteric-coated formulas are relati9ely ell tolerated and that



,5

+. rEamEn o! dru$&rESISanu"ErCu#oSIS

there is no cross-resistance to other agents" When to agents are needed+ cycloserinecan be added" 2ince the combination of ethionamide 5or ,rotionamide8 and P*2 of-

ten causes a high incidence of gastrointestinal side-eects and hy,othyroidism+ theseagents are usually used together only hen three Grou, ! agents are needed: ethion-

amide 5or ,rotionamide8+ cycloserine and P*2" Teri1idone can be used instead of cycloserine and is assumed to be e@ually eScacious"

@roup 8.Grou, / drugs are not recommended by WHO for routine use in drug-resistant T% treatment because their contribution to the eScacy of multidrug regi-

mens is unclear" They can be used in cases here it is im,ossible to design ade@uateregimens ith the medicines from Grou,s )!+ such as in ,atients ith JD?-T%" They should be used in consultation ith an eA,ert in the treatment of drug-resistant

T%"

Table ;(- groupS of drugS To TreAT mdr$TB a

$rou* drugs 8a""reviations

$rou* 1:

first$line oral agents

6 pyrainamide "Z#

6 ethambutol "e#6 rifabutin "rfb#

$rou* 2:

in3ectable agents

6 &anamycin ",m#

6 ami&acin "am#

6 capreomycin "Dm#

6 6treptomycin "s#

$rou* 3:

fluoroquinolones

6 levoo%acin "Ef%#

6 mo%io%acin "mf%#

6 oo%acin "of%#

$rou* %:

oral bacteriostatic second$line

agents

6 para$amino6alicylic acid "pas#

6 cyclo6erine "D6#

6 teriidone "trd#

6 ethionamide "eto#

6 protionamide "pto#

$rou* 5:

Agents with unclear role in

treatment of drug resistant$TB

6 clofaimine "Df#

6 lineolid "Ed#

6 amo%icillin1clavulanate "am%1Dlv#

6 thioacetaone "th#

6 imipenem1cila6tatin "ipm1Dln#

6 high$do6e i6oniaid "high$do6e H# b

6 clarithromycin "Dlr#

a Adapted from Table ;(- and figure ;(2 of reference )(b High$dose isoniaid is de0ned as -7528 mg1&g1day( Some e%perts recommend using high$dose

isoniaid in the presence of resistance to low concentrations of isoniaid "O-I of bacilli resistant to

8(2 Pg1ml but susceptible to - Pg1ml of isoniaid#! whereas isoniaid is not recommended for high$

dose resistance "O-I of bacilli resistant to - Pg1ml of isoniaid# ")#(



,)


+.% $enera# *rinci*#es in designing an mdr&" treatment regimen

The general ,rinci,les in Table 3"& a,,ly hether an .TP manager is selecting anem,irical or standard $D?-T% regimen for the country or a clinician is construct-)

ing a regimen for an indi9idual ,atient" These ,rinci,les also a,,ly to JD?-T% cases"50ndi9idual ,atient-s,eci6c information+ hich is ,art of the clinicianBs e9aluation of each ,atient before starting the $D? regimen+ is gi9en in ,arentheses in the table"8

Treatment regimens should consist of at least four drugs ith either certain+ or al-most certain+ eecti9eness" Where e9idence about the eecti9eness of a certain drug

is unclear+ the drug can be ,art of the regimen but it should not be de,ended u,onfor success" Often+ more than four drugs may be started if the susce,tibility ,attern is

un=non or the eecti9eness of one or more agents is @uestionable"

2usce,tibility testing for isonia1id+ rifam,icin+ the [uoro@uinolones+ and the inEect-able agents is fairly reliable" For other agents it is less reliable+ and basing indi9idual-i1ed treatments on D2T for these agents should be a9oided" The clinical eecti9eness

or ineecti9eness of a drug cannot be ,redicted by D2T ith )''V certainty"

ach dose in an $D? regimen is gi9en as DOT throughout the treatment" 2ee refer-ence)for detailed information on each drug+ including ad9erse eects+ contraindica-tions+ monitoring+ and dosing based on eight bands"

+.5 rogrammatic strategies !or treatment o! mdr&"Programmatic a,,roaches to $D?-T% treatment de,end in ,art on the ty,e of labo-ratory method used to con6rm $D? 5see Figure 3")8" Once $D?-T% is con6rmed 5by

either ty,e of laboratory method8+ ,atients can be treated ith:

a standard $D? regimen 5standardi1ed a,,roach8< or an indi9idually tailored regimen+ based on D2T of additional drugs"

For .TPs using con9entional D2T methods+ there is often a delay of months beforeresults are a9ailable to con6rm or eAclude $D?" These countries need to consider

$D? treatment at to stages: hen $D? is sus,ected but laboratory con6rmationis ,ending+ and once $D? is con6rmed" While aaiting results+ ,atients ho are

highly li=ely to ha9e $D?-T% 5such as those hose ,rior treatment has failed8 needan em,irical $D? regimen" 0f $D? is con6rmed+ this regimen may be continued+

or it may be tailored on the basis of susce,tibility to drugs other than isonia1id andrifam,icin+ as discussed in section 3"3"

.TPs using ra,id molecular-based D2Till be able to con6rm $D?-T% ithin )&days+ and then can initiate treatment ith a standard $D? regimen immediately+ or&

)Programmatic strategies for $D?-T% treatment 5standardi1ed or indi9iduali1ed a,,roaches8 aredescribed in section 3"/"

&Line ,robe assays detect resistance to rifam,icin alone or in combination ith isonia1id resistance"O9erall high accuracy for detection of $D? is retained hen rifam,icin resistance alone is used as a

mar=er for $D? 5+!8"



,+

may tailor the regimen later hen D2T results for second-line drugs become a9ail-able+ as discussed in section 3"3"

2tandardi1ed and indi9iduali1ed a,,roaches each ha9e ad9antages" 2tandard $D?- T% regimens 5/8ma=e it easier to estimate drug needs+ to order+ manage and dis-

tribute drug stoc=s+ and to train ,ersonnel in the treatment of $D?-T% ,atients"9en hen standard regimens are used throughout treatment+ ,atients eA,eriencingse9ere ad9erse eects ill need to ha9e their $D? treatment indi9iduali1ed" Thus all

,rogrammes need some ca,acity to indi9iduali1e treatment"


Table ;(2 generAl principleS for deSigning mdr$TB TreATmenT

regimenS a

rinci*#es Comments

-( use at least 4 drugs certainto be effective

The more of the following factors are present! the more li&elyit is that the drug will be effective+

6 re6i6tance to the6e drug6 i6 &nown from 6urvey6 to be

rare in similar patients(

6 st re6ult6 6how 6u6ceptibility to drug6 for which there

is good laboratory reliability+ in3ectable agents and

uoroquinolones(

6 the drug i6 not commonly u6ed in the area(

6 "For decisions about an individual patient 5 no prior

history of treatment failure with the drug no &nown close

contacts with resistance to the drug(#

2( do not use drugs for which

there is the possibility of

cross$resistance

6 many antituberculo6i6 agent6 e%hibit cro66$re6i6tance

both within and across drug classes "see section ;()#(

)( eliminate drugs that are not

safe

6 Quality of the drug i6 un&nown(

6 "For decisions about an individual patient 5 &nown severe

allergy or unmanageable intolerance high ris& of severe

adverse drug effects such as renal failure! deafness!

hepatitis! depression and1or psychosis(#

4( include drugs from groups-5* in a hierarchical order

based on potency "see

Table ;(- and section ;()#

6 u6e any of the r6t$line oral agent6 "Rroup -# that areli&ely to be effective(

6 u6e an effective aminoglyco6ide or polypeptide by

in3ection "group 2#( b

6 u6e a uoroquinolone "Rroup S#(

6 u6e the remaining Rroup 4 drug6 to complete a regimen of

at least four effective drugs(

6 For regimen6 with fewer than four effective drug6!

consider adding two group * drugs( The total number

of drugs will depend on the degree of uncertainty! and

regimens often contain 0ve to seven(

a Adapted from Table ;() of reference )(b Avoid streptomycin even if dST suggests susceptibility because of high rates of resistance with resis$

tant TB strains and higher incidence of ototo%icity(



,,


Changing to anindi9iduali1edregimen 5once D2T results are a9ailable for additionaldrugs beyond isonia1id and rifam,icin8 is ad9antageous because it:

X*llos clinicians Xo design a regimen iXh =noledge of resisXance Xo ,arXicular

inEectables and [uoro@uinolones+ hich is es,ecially im,ortant if ,atients ha9erecei9ed second-line drugs in the ,ast" This =noledge hel,s in a9oiding the use

of toAic and eA,ensi9e drugs to hich the ,atientBs$" tuberculosisis found to beresistant"

X*llos clinicians Xo Xailor Xhe regimen in seXXings iXh high raXes of resisXance Xosecond-line drugs here it may be diScult to 6nd a standard regimen that is a,-

,ro,riate for all ,atients"

XPro9ides eAibiliXy if ,aXienXs eA,erience ad9erse eecXs relaXed Xo one drug"

0n some settings+ indi9iduali1ed regimens may achie9e higher cure rates than stand-ard $D? regimens 578"

figure ;(- diAgrAm of mdr TreATmenT STrATegieS depending on

lABorATory meTHod To confirm mdr

reatment time#ine 8time since " diagnosis

" diagnosis $$$$$$$ 1$$$$$$$$1$$$$$$$1$$$$$$$1$$$$$$$1$$$$$$$1$$$$$$$1$$$$$$$1$$$$$$$1$$$$$$$1$$$$

,ountries using con&entional methods to detect M$%!

hi#e a/aiting dS resu#ts !or isoniaid=ri!am*icin>

mdr&" is sus*ected

once mdr is confirmed

m,iricaltreatment with mdr regimen continue standardmdr regimen

or

change to indi9iduali1edmdr regimen

"once susceptibility testing for second$line

drugs is available#

,ountries using ra#id method to detect M$%!

once mdr is confirmed a

2tandardmdr regimen

or

0ndi9iduali1edmdr regimen "once susceptibility testing for second$line drugs is available#

a little waiting ta&es appro%imately -52 days to detect mdr(



,9

+.) Se#ection o! the country<s standard mdr&" regimen

* countryBs standard $D? regimen can be used hile con6rmation of $D? isaaited 5i"e" em,irically8 or once $D? is con6rmed" 0n selecting the standard $D?

regimen+ .TP managers are strongly urged to see= eA,ert consultation 5see section3"& abo9e8 and to re9ie ,lanned regimens 5)8"The discussion belo ,ro9ides a gen-eral o9er9ie only"

The standard $D? regimen is constructed using the ,rinci,les outlined in section3"/ and Table 3"&" To identify the drugs that are li=ely to be eecti9e+ the .TP man-

ager needs to gather information about the le9el of $D? in the ,atients to be treated+as ell as the ,attern of resistance to other Grou, ) drugs+ inEectable agents 5Grou,

&8and [uoro@uinolones 5Grou, 8" 0deally+ drug resistance data ill be a9ailable from

,atients ho ha9e similar histories of ,re9ious treatment to the ,atients ho illactually be treated" The data should:

include a large enough number of ,atients to gi9e con6dence in the results< be based on reliable laboratory methods for D2T<

accurately describe the ,atientsB treatment history to distinguish beteen thosein hom the 6rst or subse@uent treatment failed+ those ho ha9e rela,sed+ and

those ho are returning after defaulting"

*s described in section "4"&+ the .TP manager should access any drug resistance

sur9eys or a9ailable sur9eillance data" 0f data sho 9ery dierent drug resistance ,at-terns across grou,s of ,re9iously treated ,atients+ there may need to be more thanone standard $D? regimen"

The .TP manager also needs to assess the use and @uality of anti-T% drugs in thecountry" The folloing information+ if a9ailable+ ill be hel,ful:

XCurrenX and ,asX .TP sXandard regimens for ne and ,re9iously XreaXed ,aXienXs"

XHisXory of drug a9ailabiliXy and sales in ,harmacies" 2ome second line anXi-T%drugs may ha9e been used only rarely and ill ,robably be eecti9e in $D? regi-

mens" Those that ha9e been used eAtensi9ely are highly li=ely to be ineecti9e"

XIualiXy assurance of drugs used iXhin and ouXside Xhe .TP"

%oA 3") ,ro9ides an eAam,le of ho to design a standard regimen"

+.+ Se#ection o! individua#ied mdr&" regimens

0ndi9idually designed regimens are based on the ,atientBs history of ,ast drug useand on D2T of isonia1id+ rifam,icin+ the second-line inEectable agents and a [uoro-

@uinolone" 9ery eort should be made to su,,lement the ,atientBs memory of treat-ment ith obEecti9e records from ,re9ious health care ,ro9iders" * detailed clinicalhistory can hel, suggest hich drugs are li=ely to be ineecti9e" *lthough resistancecan de9elo, in less than ) month+ if a ,atient has used a drug for more than ) month




9-


ith ,ersistently ,ositi9e smears or cultures+ the strain should as a general rule beconsidered as ,robably resistantQ to that drug+ e9en if D2T results indicate that it is

susce,tible"D2T results should com,lement+ rather than in9alidate+ other sources of data on the

li=ely eecti9eness of a s,eci6c drug" For eAam,le+ if a history of ,rior anti-T% druguse suggests that a drug is li=ely to be ineecti9e+ that drug should not be relied onas one of the four core drugs in the regimen+ e9en if D2T shos the strain to be sus-

ce,tible" *lternati9ely+ if the ,atient has ne9er ta=en a ,articular drug and resistanceto that drug is eAtremely uncommon in the community+ D2T results that indicate

resistance may be the result case of a laboratory error or of the limited s,eci6city of

D2T for some second-line drugs")

)2ince a [uoro@uinolone and an inEectable agent form the bac=bone of $D? treatment+ they should beused e9en if the ,atientBs$" tuberculosisdemonstrates resistance to all a9ailable drugs in these toclasses 53+48"

ox +.1

e%Ample a

Survey data from :) consecutively enrolled relapsed patients from a resource$

constrained area show that --I have mdr$TB( of these mdr$TB cases! 4*I are resis$

tant to ethambutol and 2:I are resistant to streptomycin( resistance to other drugs is

un&nown however! there is virtually no use of any of the second$line drugs in the area(

what retreatment strategy is recommended in this group of relapse patientsN

given the relatively low rate of mdr$TB in this group! the following strategy is planned+

6 All relapse patients will be started on isoniaid! rifampicin! pyrainamide! ethambutol

and streptomycin! i(e( the retreatment regimen using 0rst$line drugs(

6 dST of isoniaid and rifampicin will be done at the start of treatment to identify the

--I of mdr$TB patients who will not do well on the retreatment regimen of 0rst$linedrugs(

6 Those patients identi0ed with mdr$TB will be switched to the standard regimen+

9 months of pyrainamide! &anamycin! oo%acin! protionamide! and cycloserine!

followed by -2 months of oo%acin! protionamide! and cycloserine(

The regimen contains four drugs rarely used in the area and is also relatively ine%$

pensive(

6 A small dST survey is planned to document the prevalence of resistance to the regi$

menGs 0ve drugs in )8 relapse patients found to have mdr$TB( if this survey shows

high resistance to any of the proposed drugs! redesign of the regimen will be consid$

ered(

Note+ The regimen proposed in this answer is only one e%ample of an adequate regimen(

a reproduced from uidelines "or the #rogrammatic management o" drug-resistant tuberculosis!

emergency u#date 2008 ")#(



91

*nother im,ortant limitation is the turnaround time for D2T results: the ,atient mayha9e already recei9ed months of treatment by the time D2T results become a9ailable

from the laboratory" The ,ossibility of further ac@uired resistance de9elo,ing dur-ing this time must be considered" 0f there is a high ,robability of ac@uired resistance

to a ,articular drug after collection of the s,ecimen for D2T+ that drug should notbe counted as one of the four drugs in the core regimen 5but can be included as an

adEuncti9e agent8"

+., monitoring the mdr&" *atient

Close monitoring is essential during treatment of $D?-T% ,atients" To assess treat-ment res,onse+ s,utum smears and cultures should be ,erformed monthly until

smear and culture con9ersion" 5Con9ersion is de6ned as to consecuti9e negati9e

smears and cultures ta=en ' days a,art"8 *fter con9ersion+ the minimum fre@uencyrecommended for bacteriological monitoring is monthly for smears and @uarterly for

cultures" $onitoring of $D?-T% ,atients by a clinician should be at least monthlyuntil s,utum con9ersion+ then e9ery & months" ach ,atientBs eight should be

monitored monthly"

2econd-line drugs ha9e many more ad9erse eects than the 6rst-line anti-T% drugs+but management of these ad9erse eects is ,ossible e9en in resource-,oor settings" *t

e9ery DOT and clinician encounter+ the ,atient should be screened for side-eects of

medication" 0t is also essential for ,atients to be aare of ,ossible side-eects and toha9e access to clinical and laboratory ser9ices to hel, detect side-eects+ and medica-tions to treat ad9erse eects hen they occur" For more details on ,atient monitoring+

see reference)" Timely and intensi9e monitoring for+ and management of+ ad9erseeects caused by second-line drugs are essential for $D?-T% treatment"

+.9 duration o! treatment !or mdr&"

0n $D?-T% treatment+ the intensi9e ,hase is de6ned by the duration of treatmentith the inEectable agent" The inEectable agent should be continued for a minimum

of 7 months+ and for at least ! months after the ,atient 6rst becomes and remainssmear- or culture-negati9e" ?e9ie of the ,atientBs cultures+ smears+ J-rays and clini-cal status may also aid in deciding hether or not to continue an inEectableagentlonger than the abo9e recommendation+ ,articularly in the case of ,atients for hom

the susce,tibility ,attern is un=non+ eecti9eness of one or more agents is @uestion-able+ or eAtensi9e or bilateral ,ulmonary disease is ,resent"

Culture con9ersion also determines the o9erall duration of $D? treatment" Theseguidelines recommend continuing thera,y for a minimum of )4 months after culture

con9ersion" Atension of thera,y to &! months may be indicated in chronic casesith eAtensi9e ,ulmonary damage"




92


+.1- reating " /ith resistance *atterns other than mdr

Cases ith drug resistance ,atterns other than $D? ill be detected by D2T" Thedesign of regimens for mono- and ,oly-resistant cases of T% is recommended for

,rogrammes ith good infrastructure that are ca,able of treating $D?-T%" 0ndi-9idually designed treatments for mono- and ,oly-resistance are often determined bya re9ie ,anel that meets ,eriodically" The ,anel re9ies treatment history+ D2T ,at-

terns and the ,ossibility of strains of $" tuberculosisha9ing ac@uired ne resistance+and then determines the regimen" For suggested regimens according to the ,attern

of drug resistance+ see reference)"

0t is essential to remember that the D2T result re[ects the bacterial ,o,ulation at thetime the s,utum as collected and not necessarily the bacterial ,o,ulation in the ,a-

tient at the time the result is re,orted" During the inter9al beteen collection of thes,ecimen and recei,t of the results+ the$" tuberculosisbacteria may ha9e ac@uiredfurther resistance if the ,atient as being treated ith the functional e@ui9alent of only one drug for a signi6cant ,eriod of time 5usually considered to be ) month or

more8" De,ending on the drugs concerned+ resistance sometimes de9elo,s if the,atient as recei9ing the functional e@ui9alent of to drugs" For eAam,le+ ,yra1i-

namide is not considered a good com,anion drug to ,re9ent resistance 5)+ (8" 0f a,atient as functionally recei9ing only rifam,icin and ,yra1inamide in the initial

,hase 5because of resistance to isonia1id and ethambutol8+ resistance to rifam,icin

may de9elo,"

+.11 recording and re*orting drug&resistant " cases=

eva#uation o! outcomes

?ecording and re,orting acti9ities assist in the management of indi9idual ,atientsand enable managers to e9aluate and im,ro9e the treatment outcomes of the,ro-gramme as a hole" * system other than the standard one for drug-susce,tible T%

is recommended for drug-resistant T% cases" For registration of ,atients ith drugresistance and for re,orting treatment outcome for $D? ,atients+ the reader is re-

ferred to reference)"

re!erences

Guidelines for the ,rogrammatic management of drug-resistant tuberculosis: emer-)"gency u,date &''4" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$# T%#&''4"!'&8"0nternational 2tandards for Tuberculosis Care 502TC8&" + &nd ed" The Hague+ Tuberculo-sis Coalition for Technical *ssistance+ &''("

$olecular line ,robe assays for ra,id screening of ,atients at ris= of $D?-T%: ,olicy" statement"Gene9a+ World Health Organi1ation+ &''4 5a9ailable at: "ho"int#tb#featuresYarchi9e#,olicyYstatement",df8"

2am 0C et al" $ycobacterium tuberculosis and rifam,in resistance+ Mnited Ningdom"!"merging 0nfectious Diseases+ &''7+ )&:3/&3/("



93

2uare1 PG et al" Feasibility and cost-eecti9eness of standardi1ed second-line drug/"treatment for chronic tuberculosis ,atients: a national cohort study in Peru"Lancet+&''&+ /(:)(4')(4("?esch 2C et al" Cost-eecti9eness of treating multidrug-resistant tuberculosis"7" PLo2

$edicine+ &''7+ 538:e&!)"Nesha9Eee 2 et al" Treatment of eAtensi9ely drug-resistant tuberculosis in Toms=+3"

?ussia: a retros,ecti9e cohort study"Lancet+ &''4+ 3&:)!')!'("$itnic= CD et al" Com,rehensi9e treatment of eAtensi9ely drug-resistant tuberculo-4"

sis".e ngland ournal of $edicine+ &''4+ /(:/7/3!"$itchison D*" %asic mechanisms of chemothera,y"(" Chest+ )(3(+ 3757 2u,,l"8:33)34)"




95

,

Treatment of eAtra,ulmonary T%and of T% in s,ecial situations

,.1 Cha*ter o"4ectives


the treatment of eAtra,ulmonary T%< im,ortant drug interactions< the treatment of T% in ,regnancy and breastfeeding<

the treatment of ,atients ith ,re-eAisting li9er disease+ renal failure or renalinsuSciency"

,. 2 reatment o! extra*u#monary "

*lthough T% most commonly aects the lungs+ any organ or tissue can be in9ol9ed"0n countries ith com,rehensi9e diagnostic and re,orting systems+ eAtra,ulmonary

T% accounts for &'&/V of re,orted cases" Globally+ eAtra,ulmonary cases 5ithoutconcurrent ,ulmonary in9ol9ement8 com,rised )!V of noti6ed cases 5ne and re-la,se8 in &''3" Of s,eci6c forms of PT%+ lym,hatic+ ,leural+ and bone or Eoint dis-

ease are the most common+ hile ,ericardial+ meningeal and disseminated 5miliary8forms are more li=ely to result in a fatal outcome"

*s discussed in Cha,ter /+ ,ro9ider-initiated H0 testing is recommended as ,artof the e9aluation of all T% ,atients and ,atients in hom the disease is sus,ected"

H0 testing is es,ecially im,ortant in ,ersons ith or sus,ected of ha9ing PT%because of the increased fre@uency of eAtra,ulmonary in9ol9ement in ,ersons ith

immunosu,,ression" Atra,ulmonary T% is considered to be WHO clinical stage !H0 disease 5)8"5$ore details on the treatment of T% in ,ersons li9ing ith H0 are

,ro9ided in Cha,ter /"8

For WHO guidance on the ,rom,t diagnosis of PT%+ see reference)"

Pulmonary and eAtra,ulmonary disease should be treated ith the same regimens5see Cha,ter 8" .ote that some eA,erts recommend ()& months of treatment for)

T% meningitis 5&+ 8gi9en the serious ris= of disability and mortality+ and ( monthsof treatment for T% of bones or Eoints because of the diSculties of assessing treatment

res,onse 58"Mnless drug resistance is sus,ected+ adEu9ant corticosteroid treatmentis recommended for T% meningitis and ,ericarditis 5)!8"0n tuberculous meningitis+ethambutol should be re,laced by stre,tomycin"

) This fourth edition no longer includes the o,tion of omitting ethambutol during the intensi9e ,hase of treatment for ,atients ith eAtra,ulmonary disease ho are =non to be H0-negati9e"



9)


*lthough sometimes re@uired for diagnosis+ surgery ,lays little role in the treatmentof eAtra,ulmonary T%" 0t is reser9ed for management of late com,lications of disease

such as hydroce,halus+ obstructi9e uro,athy+ constricti9e ,ericarditis and neuro-logical in9ol9ement from PottBs disease 5s,inal T%8" For large+ [uctuant lym,h nodesthat a,,ear to be about to drain s,ontaneously+ as,iration or incision and drainage

a,,ear bene6cial 58"

,.3 Im*ortant drug interactions

$any T% ,atients ha9e concomitant illnesses" *t the start of T% treatment+ all ,a-tients should be as=ed about medicines they are currently ta=ing" The most im,ortant

interactions ith anti-T% drugs are due to rifam,icin" ?ifam,icin induces ,athaysthat metaboli1e other drugs+ thereby reducing the concentration and eect of those

drugs" To maintain a thera,eutic eect+ dosages of the other drug5s8 may need to beincreased" When rifam,icin is discontinued+ its metabolism-inducing eect resol9es

ithin about & ee=s+ and dosages of the other drug5s8 ill need to be reduced 58"

$ore information on T% drug interactions is a9ailable in *nneA ) and on the ebsites of the Global Drug Facility and the WHO ssential $edicines Library 5"

sto,tb"org#gdf#drugsu,,ly#drugsYa9ailable"as, and "ho"int#emlib#$edicines"as,A8"

?ifam,icin substantially reduces the concentration and eect of the folloing drugs

5for recommendations on dosage adEustment and on clinical or thera,eutic drugmonitoring+ see reference8:

anti-infecti9es 5including certain antiretro9iral drugs discussed in section /"7")+me[o@uine+ a1ole antifungal agents+ clarithromycin+ erythromycin+ doAycycline+

ato9a@uone+ chloram,henicol8< hormone thera,y+) including ethinylestradiol+ norethindrone+ tamoAifen+

le9othyroAine< methadone<

arfarin< cyclos,orin< corticosteroids< anticon9ulsants 5including ,henytoin8<

cardio9ascular agents including digoAin 5among ,atients ith renal insuS-ciency8+ digitoAin+ 9era,amil+ nifedi,ine+ diltia1em+ ,ro,ranolol+ meto,rorol+

enala,ril+ losartan+ @uinidine+ meAiletine+ tocainide+ ,ro,afenone< theo,hylline< sulfonylurea hy,oglycaemics<

)?ifam,icin interacts ith oral contrace,ti9e medications leading to loered ,rotecti9e eScacy" *oman recei9ing oral contrace,tion may choose beteen to o,tions hile recei9ing treatment ith

rifam,icin: folloing consultation ith a clinician+ an oral contrace,ti9e ,ill containing a higher es-trogen dose 5/' ]g8+ or another form of contrace,tion"



9+

,. rEamEn o! Exrau#monary " and o! " In SECIa# SIuaIonS

hy,oli,idaemics including sim9astatin and [u9astatin< nortri,tyline+ halo,eridol+ @uetia,ine+ ben1odia1e,ines 5including dia1e,am+

tria1olam8+ 1ol,idem+ bus,irone"

,. % reatment regimens in s*ecia# situations

The treatment of T% in ,regnancy and breastfeeding+ li9er disorders+ and renal fail-ure is discussed belo"

9(4(- pregnancy and breastfeeding

Women of childbearing age should be as=ed about current or ,lanned ,regnancybefore starting T% treatment" * ,regnant oman should be ad9ised that successful

treatment of T% ith the standard regimen is im,ortant for successful outcome of ,regnancy" With the eAce,tion of stre,tomycin+ the 6rst line anti-T% drugs are safe

for use in ,regnancy: stre,tomycin is ototoAic to the fetus and should not be usedduring ,regnancy"

* breastfeeding oman ho has T% should recei9e a full course of T% treatment" Timely and ,ro,erly a,,lied chemothera,y is the best ay to ,re9ent transmission of

tubercle bacilli to the baby" $other and baby should stay together and the baby shouldcontinue to breastfeed" *fter acti9e T% in the baby is ruled out+ the baby should be

gi9en 7 months of isonia1id ,re9enti9e thera,y+ folloed by %CG 9accination 5/8"

PyridoAine su,,lementation is recommended for all ,regnant or breastfeeding om-en ta=ing isonia1id 5see section !"48"

9(4(2 liver disorders

This section co9ers T% treatment in ,atients ith ,re-eAisting li9er disease< for detec-tion and management of he,atitis induced by anti-T% drugs+ see section !")'"&"

Patients ith the folloing conditions can recei9e the usual T% regimens ,ro9ided

that there is no clinical e9idence of chronic li9er disease: he,atitis 9irus carriage+a ,ast history of acute he,atitis+ current eAcessi9e alcohol consum,tion" Hoe9er+he,atotoAic reactions to anti-T% drugs may be more common among these ,atients

and should therefore be antici,ated 5see section !")'"&8"

0n ,atients ith unstable or ad9anced li9er disease+ li9er function tests should bedone at the start of treatment+ if ,ossible" 0f the serum alanine aminotransferase le9el

578is more than times normal before the initiation of treatment+ the folloing)

regimens should be considered 5also discussed in section !")'"&8" The more unstable&

or se9ere the li9er disease is+ the feer he,atotoAic drugs should be used"

) .ote that T% itself may in9ol9e the li9er and cause abnormal li9er function"&0n some cases of concurrent acute 5i"e" 9iral8 he,atitis not related to T% or T% treatment+ it may be ,os-

sible to defer T% treatment until the acute he,atitis has resol9ed"



9,


Possible regimens include:

X To he,aXoXoAic drugs 5raXher Xhan Xhe Xhree in Xhe sXandard regimen8: ( months of isonia1id and rifam,icin+ ,lus ethambutol 5until or unless isoni-

a1id susce,tibility is documented8< & months of isonia1id+ rifam,icin+ stre,tomycin and ethambutol+ folloed by

7months of isonia1id and rifam,icin< 7( months of rifam,icin+ ,yra1inamide and ethambutol"

XOne he,aXoXoAic drug: & months of isonia1id+ ethambutol and stre,tomycin+ folloed by )' months of

isonia1id and ethambutol"

X.o he,aXoXoAic drugs:

)4&! months of stre,tomycin+ ethambutol and a [uoro@uinolone"

A,ert consultation is ad9isable in treating ,atients ith ad9anced or unstable li9erdisease"

Clinical monitoring 5and li9er function tests+ if ,ossible8 of all ,atients ith ,re-eAisting li9er disease should be ,erformed during treatment"

9(4() renal failure and severe renal insuf0ciency

The recommended initial T% treatment regimen for ,atients ith renal failure orse9ere renal insuSciency is & months of isonia1id+ rifam,icin+ ,yra1inamide andethambutol+ folloed by ! months of isonia1id and rifam,icin" 0sonia1id and ri-

fam,icin are eliminated by biliary eAcretion+ so no change in dosing is necessary" There is signi6cant renal eAcretion of ethambutol and metabolites of ,yra1inamide+

and doses should therefore be adEusted" Three times ,er ee= administration of theseto drugs at the folloing doses is recommended: ,yra1inamide 5&/ mg#=g8+ and

ethambutol 5)/ mg#=g8 5+ 38"These are the same mg#=g doses as those listed underDaily in Table ")"

While recei9ing isonia1id+ ,atients ith se9ere renal insuSciency or failure shouldalso be gi9en ,yridoAine in order to ,re9ent ,eri,heral neuro,athy 5see section !"48"

%ecause of an increased ris= of ne,hrotoAicity and ototoAicity+ stre,tomycin shouldbe a9oided in ,atients ith renal failure" 0f stre,tomycin must be used+ the dosage is

)/ mg#=g+ to or three times ,er ee=+ to a maAimum of ) gram ,er dose+ and serumle9els of the drug should be monitored"



99

re!erences

ssential ,re9ention and care inter9entions for adults and adolescents li9ing ith H0)"in resource-limited settings" Gene9a+ World Health Organi1ation+ &''4"

.ational Collaborating Centre for Chronic Conditions"&" Tuberculosis: clinical diag-nosis and management of tuberculosis+ and measures for its ,re9ention and control"London+ ?oyal College of Physicians+ .0C 5.ational 0nstitute for Health and Clini-

cal Acellence8+ &''7"*merican Thoracic 2ociety+ CDC+ 0nfectious Diseases 2ociety of *merica" Treatment"

of tuberculosis"$orbidity and $ortality Wee=ly ?e,ort: ?ecommendations and ?e-,orts+ &''+ /&5??-))8:)33"

Thaites G et al" DeAamethasone for the treatment of tuberculous meningitis in!"adolescents and adults".e ngland ournal of $edicine+ &''!+ /):)3!))3/)"

Guidance for national tuberculosis ,rogrammes on the management of tuberculosis/"

in children" Gene9a+ World Health Organi1ation+ &''7 5WHO#HT$#T%#&''7"3)<WHO#FCH#C*H#&''7"38"

2au==onen et al" *n oScial *T2 statement: he,atotoAicity of antituberculo-7"sis thera,y"*merican ournal of ?es,iratory and Critical Care $edicine+ &''7+)3!:(/(/&"

Guidelines for the ,rogrammatic management of drug-resistant tuberculosis: emer-3"gency u,date &''4" Gene9a+ World Health Organi1ation+ &''4 5WHO#HT$# T%#&''4"!'&8"

,. rEamEn o! Exrau#monary " and o! " In SECIa# SIuaIonS



: :

*nneAes



1-3

a1

essential 6rst-lineantituberculosis drugs)

Isoniaid

general information

0sonia1id+ the hydra1ide of isonicotinic acid+ is highly bactericidal against re,licatingtubercle bacilli"

0t is ra,idly absorbed and diuses readily into all [uids and tissues" The ,lasma half-

life+ hich is genetically determined+ 9aries from less than ) hour in fast acetylatorsto more than hours in slo acetylators" 0sonia1id is largely eAcreted in the urine

ithin &! hours+ mostly as inacti9e metabolites"

clinical information

Administration and dosage

0sonia1id is normally ta=en orally but may be administered intramuscularly or intra-9enously to critically ill ,atients"

*dults:

/ mg#=g 5!7 mg#=g8 daily+ maAimum '' mg)' mg#=g 54)& mg#=g8 three times ee=ly+ maAimum ('' mg 5)8"

,ontraindications

XNnon hy,ersensiXi9iXy"X*cti9e+ unstable he,atic disease 5ith Eaundice8 see section 4"!"&"

recautionsClinical monitoring 5and li9er function tests+ if ,ossible8 should be ,erformed dur-

ing treatment of ,atients ith ,re-eAisting li9er disease" Patients at ris= of ,eri,heralneuro,athy+ as a result of malnutrition+ chronic alcohol de,endence+ H0 infection+

,regnancy+ breastfeeding+ renal failure or diabetes+ should additionally recei9e ,yri-doAine+ )' mg daily" Where the standard of health in the community is lo+ ,yridoA-

ine should be oered routinely" 5.ote that other guidelines 5)8 recommend a dose of &/ mg#day to ,re9ent ,eri,heral neuro,athy8" For established ,eri,heral neuro,athy+

,yridoAine should be gi9en at a larger dose of /'3/ mg daily 5&8"

)For drug ,re,arations 5include 6Aed-dose combinations8 and costs+ see the Global Drug Facility ebsite:"sto,tb"org#gdf#drugsu,,ly#drugsYa9ailable"as," 2ee alsoWHO $odel Formulary &''4:"ho"int#selectionYmedicines#list#en#



1-%


2ince isonia1id interacts ith anticon9ulsants used for e,ile,sy+ it may be necessaryto reduce the dosage of these drugs during treatment ith isonia1id" 0f ,ossible+ se-

rum concentrations of ,henytoin and carbama1e,ine should be measured in ,atientsrecei9ing isonia1id ith or ithout rifam,icin 5seeDrug interactionsbelo8"

4se in #regnancy

0sonia1id is not =non to be harmful in ,regnancy 58" PyridoAine su,,lementationis recommended for all ,regnant 5or breastfeeding8 omen ta=ing isonia1id"

Ad&erse e""ects

0sonia1id is generally ell tolerated at recommended doses"

2ystemic or cutaneous hy,ersensiti9ity reactions occasionally occur during the 6rstee=s of treatment"

2lee,iness or lethargy can be managed by reassurance or adEustment of the timing of administration"

The ris= of ,eri,heral neuro,athy is eAcluded if 9ulnerable ,atients recei9e daily su,-,lements of ,yridoAine" Other less common forms of neurological disturbance+ in-cluding o,tic neuritis+ toAic ,sychosis and generali1ed con9ulsions+ can de9elo, in

susce,tible indi9iduals+ ,articularly in the later stages of treatment+ and occasionally

necessitate the ithdraal of isonia1id"2ym,tomatic he,atitis is an uncommon but ,otentially serious reaction that canusually be a9erted by ,rom,t ithdraal of treatment" $ore often+ hoe9er+ an

asym,tomatic rise in serum concentrations of he,atic transaminases at the outset of treatment is of no clinical signi6cance and usually resol9es s,ontaneously as treat-

ment continues"

* lu,us-li=e syndrome+ ,ellagra+ anaemia+ and arthralgias are other rare ad9erse ef-fects 5&8"$onoamine ,oisoning has been re,orted to occur after ingestion of foods

and be9erages ith high monoamine content+ but this is also rare 5)8"

$rug interactions

0sonia1id inhibits the metabolism of certain drugs+ hich can increase their ,lasmaconcentration to the ,oint of toAicity" ?ifam,icin+ hoe9er+ has the o,,osite eect

for many of these drugs" For eAam,le+ the a9ailable data indicate that administeringboth rifam,icin and isonia1id causes a reduction in ,lasma le9els of ,henytoin and

dia1e,am 5)8"

0sonia1id may increase the toAicity of carbama1e,ine+ ben1odia1e,ines metaboli1edby oAidation 5such as tria1olam8+ acetamino,hen+ 9al,roate+ serotonergic antide,res-sants+ disul6ram+ arfarin and theo,hylline"



1-5

annEx 1. ESSEnIa# !IrS&#InE anIu"ErCu#oSIS dru$S

O&erdosage

.ausea+ 9omiting+ di11iness+ blurred 9ision and slurring of s,eech occur ithin 'minutes to hours of o9erdosage" $assi9e ,oisoning results in coma ,receded by

res,iratory de,ression and stu,or" 2e9ere intractable sei1ures may occur" mesis andgastric la9age+ acti9ated charcoal+ antie,ile,tics and 0 sodium bicarbonate can be of 9alue if instituted ithin a fe hours of ingestion" 2ubse@uently+ haemodialysis may

be of 9alue" High doses of ,yridoAine must be administered to ,re9ent sei1ures"

+torage

Tablets should be =e,t in ell-closed containers+ ,rotected from light" 2olution forinEection should be stored in am,oules+ ,rotected from light"

ri!am*icingeneral information

* semisynthetic deri9ati9e of rifamycin+ rifam,icin is a com,leA macrocyclic antibi-otic that inhibits ribonucleic acid synthesis in a broad range of microbial ,athogens"

0t has bactericidal action and a ,otent sterili1ing eect against tubercle bacilli in bothcellular and eAtracellular locations"

?ifam,icin is li,id-soluble" Folloing oral administration+ it is ra,idly absorbed anddistributed throughout the cellular tissues and body [uids< if the meninges are in-

[amed+ signi6cant amounts enter the cerebros,inal [uid" * single dose of 7'' mg,roduces a ,ea= serum concentration of about )' ]g#ml in &! hours+ hich subse-

@uently decays ith a half-life of & hours" 0t is eAtensi9ely recycled in the enterohe-,atic circulation+ and metabolites formed by deacetylation in the li9er are e9entually

eAcreted in the faeces"

2ince resistance readily de9elo,s+ rifam,icin must alays be administered in combi-nation ith other eecti9e antimycobacterial agents"



?ifam,icin should ,referably be gi9en at least ' minutes before meals+ since absor,-tion is reduced hen it is ta=en ith food" Hoe9er+ this may not be clinically signi6-

cant+ and food can reduce intolerance to drugs" ?ifam,icin should alays be gi9enin combination ith other eecti9e antimycobacterial agents" 0t is also a9ailable for

intra9enous administration in critically ill ,atients 5)8"

*dults:

)' mg#=g 54)& mg#=g8 daily or times ee=ly+ maAimum 7'' mg"



1-)


,ontraindications

XNnon hy,ersensiXi9iXy Xo rifamycins"X*cti9e+ unstable he,atic disease 5ith Eaundice8 see section 4"!"&"

recautions

2erious immunological reactions resulting in renal im,airment+ haemolysis orthrombocyto,enia are on record in ,atients ho resume ta=ing rifam,icin after a,rolonged la,se of treatment" 0n this rare situation+ rifam,icin should be immedi-

ately and ,ermanently ithdran"

Clinical monitoring 5and li9er function tests+ if ,ossible8 should be ,erformed duringtreatment of all ,atients ith ,re-eAisting li9er disease+ ho are at increased ris= of

further li9er damage"

Patients should be arned that treatment may cause reddish coloration of all bodysecretions 5urine+ tears+ sali9a+ seat+ semen and s,utum8+ and that contact lenses and

clothing may be irre9ersibly stained"

4se in #regnancy

itamin N should be administered at birth to the infant of a mother ta=ing rifam,icinbecause of the ris= of ,ostnatal haemorrhage"

Ad&erse e""ects

?ifam,icin is ell tolerated by most ,atients at currently recommended doses butmay cause gastrointestinal reactions 5abdominal ,ain+ nausea+ 9omiting8 and ,ruri-

tus ith or ithout rash 5)8"

Other ad9erse eects 5fe9er+ in[uen1a-li=e syndrome and thrombocyto,enia8 aremore li=ely to occur ith intermittent administration"

Afoliati9e dermatitis is more fre@uent in H0-,ositi9e T% ,atients"

Tem,orary oliguria+ dys,noea and haemolytic anaemia ha9e also been re,orted in,atients ta=ing the drug times ee=ly< these reactions usually subside if the regi-

men is changed to daily dosage"

$oderate rises in serum concentrations of bilirubin and transaminases+ hich arecommon at the outset of treatment+ are often transient and ithout clinical signi6-

cance" Hoe9er+ dose-related he,atitis can occur and is ,otentially fatal: it is there-fore im,ortant not to eAceed the maAimum recommended daily dose of 7'' mg"



1-+

$rug interactions

?ifam,icin induces he,atic en1ymes+ and may increase the dosage re@uirements of drugs metaboli1ed in the li9er 5)8+ including:

anti-infecti9es 5including certain antiretro9iral drugs discussed belo and insection /"7")+ me[o@uine+ a1ole antifungal agents+ clarithromycin+ erythromy-

cin+ doAycycline+ ato9a@uone+ chloram,henicol8< hormone thera,y+ including ethinylestradiol+ norethindrone+ tamoAifen+

le9othyroAine< methadone< arfarin< cyclos,orine< corticosteroids<

anticon9ulsants 5including ,henytoin8< cardio9ascular agents including digoAin 5in ,atients ith renal insuSciency8+

digitoAin+ 9era,amil+ nifedi,ine+ diltia1em+ ,ro,ranolol+ meto,rorol+ enala,ril+losartan+ @uinidine+ meAiletine+ tocainide+ ,ro,afenone<

theo,hylline< sulfonylurea hy,oglycaemics< hy,oli,idaemics including sim9astatin and [u9astatin<

nortri,tyline+ halo,eridol+ @uetia,ine+ ben1odia1e,ines 5including dia1e,am+

tria1olam8+ 1ol,idem+ bus,irone"2ince rifam,icin reduces the eecti9eness of oral contrace,ti9es+ omen should bead9ised to choose beteen one of to o,tions for contrace,tion" Folloing consul-

tation ith a clinician+ the ,atient may use an oral contrace,ti9e ,ill containing ahigher dose of estrogen 5/' g8< alternati9ely+ a nonhormonal method of contrace,-

tion may be used throughout rifam,icin treatment and for at least one month sub-se@uently"

Current antiretro9iral drugs 5non-nucleoside re9erse transcri,tase inhibitors and

,rotease inhibitors8 interact ith rifam,icin 5see section /"7")8" This may result inineecti9eness of antiretro9iral drugs+ ineecti9e treatment of T% or an increasedris= of drug toAicity"

%iliary eAcretion of radiocontrast media and sulfobromo,hthalein sodium may bereduced and microbiological assays for folic acid and 9itamin % disturbed"

)&

O&erdosage

Gastric la9age may be of 9alue if underta=en ithin a fe hours of ingestion" ery

large doses of rifam,icin may de,ress central ner9ous function" There is no s,eci6cantidote and treatment is su,,orti9e"




1-,


+torage

Ca,sules and tablets should be =e,t in tightly closed containers+ ,rotected fromlight"

yrainamide

general information

Pyra1inamide is a synthetic analogue of nicotinamide that is only ea=ly bactericidalagainst$" tuberculosisbut has ,otent sterili1ing acti9ity+ ,articularly in the relati9ely

acidic intracellular en9ironment of macro,hages and in areas of acute in[ammation"0t is highly eecti9e during the 6rst & months of treatment hile acute in[ammatory

changes ,ersist" 0ts use has enabled treatment regimens to be shortened and the ris=of rela,se to be reduced"

0t is readily absorbed from the gastrointestinal tract and is ra,idly distributedthroughout all tissues and [uids" Pea= ,lasma concentrations are attained in & hours

and the ,lasma half-life is about )' hours" 0t is metaboli1ed mainly in the li9er andeAcreted largely in the urine"



Pyra1inamide is administered orally"

*dults 5usually for the 6rst & or months of T% treatment8:

&/ mg#=g 5&'' mg#=g8 daily/ mg#=g 5'!' mg#=g8 times ee=ly"

,ontraindications

XNnon hy,ersensiXi9iXy"X*cti9e+ unstable he,atic disease 5ith Eaundice8 see 2ection 4"!"&"

XPor,hyria"

recautions

Patients ith diabetes should be carefully monitored since blood glucose concentra-tions may become labile" Gout may be eAacerbated" Clinical monitoring 5and li9erfunction tests+ if ,ossible8 should be ,erformed during treatment of ,atients ith

,re-eAisting li9er disease" 0n ,atients ith renal failure+ ,yra1inamide should be ad-ministered three times ,er ee=+ rather than daily 5see section 4"!" for doses8"

4se in #regnancy

The 7-month regimen based u,on isonia1id+ rifam,icin and ,yra1inamide shouldbe used hene9er ,ossible" *lthough detailed teratogenicity data are not a9ailable+

,yra1inamide can ,robably be used safely during ,regnancy 5)8"



1-9

Ad&erse e""ects

Pyra1inamide may cause gastrointestinal intolerance"

Hy,ersensiti9ity reactions are rare+ but some ,atients com,lain of slight [ushing of

the s=in"$oderate rises in serum transaminase concentrations are common during the early

,hases of treatment" 2e9ere he,atotoAicity is rare"

*s a result of inhibition of renal tubular secretion+ a degree of hy,eruricaemia usu-ally occurs+ but this is often asym,tomatic" Gout re@uiring treatment ith allo,uri-nol occasionally de9elo,s" *rthralgia+ ,articularly of the shoulders+ may occur and

is res,onsi9e to sim,le analgesics 5es,ecially as,irin8" %oth hy,eruricaemia and ar-thralgia may be reduced by ,rescribing regimens ith intermittent administration

of ,yra1inamide"

?are ad9erse e9ents include sideroblastic anaemia 5&8 and ,hotosensiti9e dermatitis5)8"

O&erdosage

Little has been recorded on the management of ,yra1inamide o9erdose" *cute li9erdamage and hy,eruricaemia ha9e been re,orted" Treatment is essentially sym,to-

matic" mesis and gastric la9age may be of 9alue if underta=en ithin a fe hours of

ingestion" There is no s,eci6c antidote and treatment is su,,orti9e"

+torage

Tablets should be stored in tightly closed containers+ ,rotected from light"

Stre*tomycin

general information

2tre,tomycin is an aminoglycoside antibiotic deri9ed from2tre,tomyces griseusthat

is used in the treatment of T% and sensiti9e Gram-negati9e infections"2tre,tomycin is not absorbed from the gastrointestinal tract but+ after intramuscu-lar administration+ it diuses readily into the eAtracellular com,onent of most bodytissues and attains bactericidal concentrations+ ,articularly in tuberculous ca9ities"Little normally enters the cerebros,inal [uid+ although ,enetration increases hen

the meninges are in[amed" The ,lasma half-life+ hich is normally & hours+ is con-siderably eAtended in the neborn+ the elderly and ,atients ith se9ere renal im,air-

ment" 2tre,tomycin is eAcreted unchanged in the urine"




11-




2tre,tomycin must be administered by dee, intramuscular inEection" 2yringes and

needles should be ade@uately sterili1ed to eAclude any ris= of transmitting 9iral ,ath-ogens" 0t is also a9ailable for intra9enous administration 5)8"

*dults:

)/ mg#=g 5)&)4 mg#=g8 daily+ or & or times ee=ly<maAimum daily dose is )''' mg"

Patients aged o9er 7' years may not be able to tolerate more than /''3/' mg daily+so some guidelines recommend reducing the dose to )' mg#=g ,er day for ,atients

in this age grou, 5)8"Patients eighing less than /' =g may not tolerate doses abo9e/''3/' mg daily")

,ontraindications

XNnon hy,ersensiXi9iXy"X*udiXory ner9e im,airmenX"X$yasXhenia gra9is"XPregnancy"

recautionsHy,ersensiti9ity reactions are rare" 0f they do occur 5usually during the 6rst ee=s

of treatment8+ stre,tomycin should be ithdran immediately" Once fe9er and s=inrash ha9e resol9ed+ desensiti1ation may be attem,ted"

%oth the elderly and ,atients ith renal im,airment are 9ulnerable to dose-relatedtoAic eects resulting from accumulation" 2tre,tomycin should be used ith caution

in ,atients ith renal insuSciency+ because of the increased ris= of ne,hrotoAicityand ototoAicity" The dose should be maintained at )&R)/ mg#=g but at a reduced fre-

@uency of & times ,er ee= 5)8"Where ,ossible+ serum le9els should be monitored,eriodically and dosage adEusted a,,ro,riately to ensure that ,lasma concentrations+as measured hen the neAt dose is due+ do not eAceed ! g#ml"

Protecti9e glo9es should be orn hen stre,tomycin inEections are administered+ toa9oid sensiti1ation dermatitis"

4se in #regnancy

2tre,tomycin should not be used in ,regnancy: it crosses the ,lacenta and can causeauditory ner9e im,airment and ne,hrotoAicity in the fetus"

) WHO ssential $edicines Library5htt,:##a,,s"ho"int#emlib#$edicineDis,lay"as,ALanguage.^$ed0D.ame)'V!'stre,tomycin<

accessed anuary &')'8"



111

Ad&erse e""ects

2tre,tomycin inEections are ,ainful" ?ash+ induration+ or sterile abscesses can format inEection sites"

.umbness and tingling around the mouth occur immediately after inEection"Cutaneous hy,ersensiti9ity reactions can occur"

0m,airment of 9estibular function is uncommon ith currently recommended doses"Hearing loss is less common than 9ertigo" $anifestations of damage to the 4th cra-nial 5auditory8 ner9e include ringing in the ears+ ataAia+ 9ertigo and deafness< dam-

age usually occurs in the 6rst & months of treatment and is re9ersible if the dosage isreduced or the drug is sto,,ed 5&8"

2tre,tomycin is less ne,hrotoAic than other aminoglycoside antibiotics" 0f urinaryout,ut falls+ albuminuria occurs or tubular casts are detected in the urine+ stre,to-mycin should be sto,,ed and renal function should be e9aluated"

Haemolytic anaemia+ a,lastic anaemia+ agranulocytosis+ thrombocyto,enia andlu,oid reactions are rare ad9erse eects"

$rug interactions

Other ototoAic or ne,hrotoAic drugs should not be administered to ,atients recei9ingstre,tomycin" These include other aminoglycoside antibiotics+ am,hotericin %+ cefa-

los,orins+ etacrynic acid+ cyclos,orin+ cis,latin+ furosemide and 9ancomycin"

2tre,tomycin may ,otentiate the eect of neuromuscular bloc=ing agents adminis-tered during anaesthesia"

O&erdosage

Haemodialysis can be bene6cial" There is no s,eci6c antidote and treatment is su,-,orti9e"

+torage

2olutions retain their ,otency for !4 hours after reconstitution at room tem,eratureand for u, to )! days hen refrigerated" Poder for inEection should be stored in

tightly closed containers+ ,rotected from light"

Etham"uto#

general information

* synthetic congener of )+&-ethanediamine+ ethambutol is acti9e against$" tuber-

culosis+ $" bo9isand some nons,eci6c mycobacteria" 0t is used in combination ithother anti-T% drugs to ,re9ent or delay the emergence of resistant strains"

0t is readily absorbed from the gastrointestinal tract" Plasma concentrations ,ea= in&! hours and decay ith a half-life of ! hours" thambutol is eAcreted in the




112


urine both unchanged and as inacti9e he,atic metabolites" *bout &'V is eAcretedunchanged in the faeces"

clinical information Administration and dosage

thambutol is administered orally"

*dults:

)/ mg#=g 5)/&' mg#=g8 daily

' mg#=g 5&// mg#=g8 times ee=ly"

Dosage must alays be carefully calculated on a eight basis to a9oid toAicity+ and

the dose or the dosing inter9al should be adEusted in ,atients ith im,aired renalfunction 5creatinine clearance \3' ml#min8" 0f creatinine clearance is less than ' ml#minute+ ethambutol should be administered times ,er ee= 5see section 4"!"8 5)8"

,ontraindications

XNnon hy,ersensiXi9iXy"XPre-eAisXing o,Xic neuriXis from any cause"

recautions

Patients should be ad9ised to discontinue treatment immediately and to re,ort toa clinician if their sight or ,erce,tion of colour deteriorates" Ocular eAamination is

recommended before and during treatment 58" Whene9er ,ossible+ renal functionshould be assessed before treatment" Plasma ethambutol concentration should be

monitored if creatinine clearance is less than ' ml#min"

4se in #regnancy

thambutol is not =non to be harmful in ,regnancy 58"

Ad&erse e""ects

Dose-de,endent o,tic neuritis can result in im,airment of 9isual acuity and colour9ision in one or both eyes" arly changes are usually re9ersible+ but blindness can

occur if treatment is not discontinued ,rom,tly" Ocular toAicity is rare hen etham-butol is used for & months at recommended doses"

2igns of ,eri,heral neuritis occasionally de9elo, in the legs"

Other rare ad9erse e9ents include generali1ed cutaneous reaction+ arthralgia and+

9ery rarely+ he,atitis"



113

O&erdosage

mesis and gastric la9age may be of 9alue if underta=en ithin a fe hours of inges-tion" 2ubse@uently+ dialysis may be of 9alue" There is no s,eci6c antidote and treat-

ment is su,,orti9e"

+torage

Tablets should be stored in tightly closed containers"

re!erences

*merican Thoracic 2ociety+ CDC+ 0nfectious Diseases 2ociety of *merica" Treatment)"of tuberculosis"$orbidity and $ortality Wee=ly ?e,ort: ?ecommendations and ?e-,orts+ &''+/&5??-))8:)33"

Toman N"&" TomanBs tuberculosis" Case detection+ treatment+ and monitoring: @uestionsand ansers+ &nd ed" Gene9a+ World Health Organi1ation+ &''!"WHO $odel Formulary &''4" " Gene9a+ World Health Organi1ation+ &''( 5a9ailableat "ho"int#selectionYmedicines#list#W$F&''4",df8"




115

a2

summary of e9idence andconsiderationsunderlying the recommendations

With in,ut from the Guidelines Grou,+ WHO 6nali1ed a list of se9en =ey @uestionson the treatment of T%" 2ystematic literature re9ies ere conducted for each @ues-

tion and the e9idence as synthesi1ed"

The e9idence is summari1ed for each @uestion and is folloed by a descri,tion of thebene6ts+ harms+ and other considerations used in de9elo,ing the recommendations

and rating them as strong or conditional using the G?*D system 52ee Cha,ter )+section )"7 for a descri,tion of the methodology+ including de6nitions of strongQ+conditionalQ and ea=Q8" *t the time of ,ublication of this fourth edition+ e9idence

gathered through some of the systematic re9ies had not been ,ublished")

2ome of the remar=s listed in the Aecuti9e 2ummary under each recommendationare included in the Other considerations section for each @uestion belo" Where e9i-

dence is lac=ing+ future research is suggested 5*nneA /8"

uestion 1. duration o! ri!am*icin

2hould ne ,ulmonary T% ,atients be treated ith the 7-month or the &-monthrifam,icin regimen

Summary of evidence

* systematic re9ie and meta-analysis included &) !3& ,artici,ants in )& arms of /3randomi1ed controlled trials 5?CTs8 conducted in 9arious regions of the orld since

)(7/ 5)8"0n three of the /3 trials+ ,atients ere randomly assigned to either a &-monthrifam,icin or a 7-month rifam,icin arm< rates of failure+ rela,se and ac@uired drug

resistance ere com,ared head-to-headQ across the to study arms" 0n a multi9ari-ate regression analysis+ each arm of the /3 ?CTs as treated as a se,arate cohort+ and

results ere adEusted for ,otentially confounding ,atient and treatment factors"

Bene0ts and harms of changing to the 7$month rifampicin regimen

The three studies ith head-to-head com,arisons shoed that the ris= of rela,seafter a 7-month rifam,icin regimen as signi6cantly loer than that after a &-month

rifam,icin regimen" 0f a country ere to change from a &-month to a 7-month

rifam,icin regimen+ the bene6t ould be an estimated ))& rela,ses a9erted ,er )''' T% ,atients"

) G?*D tables for un,ublished e9idence are a9ailable from WHO u,on re@uest"



11)


?egression analysis suggests that changing to a 7-month regimen ould signi6cantlyreduce failure and ac@uired drug resistance rates+ in addition to rela,se rates" This)

analysis found that regimens ith /3 months of rifam,icin ha9e '"! times thefailure rate of those ith )& months of rifam,icin+ and '"& times the rela,se rate"*mong the failures and rela,ses from regimens ith /3 months of rifam,icin+ the

rate of ac@uired drug resistance is '"&4 times that of the regimens ith )& monthsof rifam,icin"

Patients ith isonia1id resistance ould reali1e maEor bene6ts if the &-monthrifam,icin regimen ere re,laced ith a 7-month regimen" *mong ,atients ithisonia1id mono-resistance at the start of treatment+ 4V rela,sed after treatment ith

&-month rifam,icin regimens+ hich is signi6cantly higher than the /"/V rela,se rateafter treatment ith 7-month rifam,icin regimens" Thus+ changing to the 7-month

rifam,icin regimen ould a9ert &/ rela,ses ,er )''' ,atients ho start treatment&

ith isonia1id resistance"

9en for ,atients ith ,an-susce,tible T%+ the ,ro,ortion ho rela,sed after the&-month rifam,icin regimen as 4"&V+ signi6cantly higher than the ")V for the7-month rifam,icin regimen"

When the 6rst course of thera,y is considered along ith retreatment for ,atientsho fail or rela,se+ it is estimated that the 7-month rifam,icin regimen ould a9ertbeteen and )& deaths ,er )''' com,ared ith the &-month rifam,icin regimen

across 3 countries modelled ith a range of drug resistance among ne ,atients" 0naddition+ '"7!"! failures and rela,ses ith drug resistance other than $D? ould

be a9erted ,er )''' T% ,atients+ but an additional '"7)" $D?-T% cases ould begenerated"

*mong ,atients ho failed or rela,sed after their 6rst course of treatment contain-ing 7 months of rifam,icin+ regression analysis found a reduction in o9erall ac@uireddrug resistance< hoe9er+ the ,attern of ac@uired drug resistance as dierent from

that in ,atients ho recei9ed the &-month rifam,icin regimen" The ris= of ac@uiring

drug resistance other than $D? is higher ith the &-month rifam,icin regimen+ butthe ris= of ac@uiring $D? is higher ith the 7-month rifam,icin regimen" *mongfailures+ the ,ro,ortion ith $D? is ,redicted to be !/7V after initial treatment

ith the &-month rifam,icin regimen but /'(!V after initial treatment ith theregimen containing 7 months of rifam,icin"

other considerations

To hel, minimi1e the ac@uisition of $D?+ it is critically im,ortant that .TPs en-

sure ade@uate su,er9ision of rifam,icin" 0m,lementing ,atient su,er9ision for the!-month continuation ,hase ill re@uire additional resources in areas here the

) The dierence in failure and ac@uired drug resistance as not statistically signi6cant in these three?CTs"

& 4 minus /"/ ,er )'' &/ ,er )'''"



11+

annEx 2. Summary o! E(IdEnCE and ConSIdEraIonS undEr#yIn$'E rECommEndaIonS

continuation ,hase has been self-administered an in9estment that may be osetby the sa9ings from rela,ses 5and therefore retreatments8 a9erted" 0n &''4+ & coun-

tries 5including ! that are considered high-burden8 still used the &-month rifam,icinregimen for their ne ,atients" These countries re,orted 3'7 ('/ ne cases in &''3+

or )V of the global ne T% noti6cations that year" *nother resource considerationis the fact that hen ,urchased through the Global Drug Facility+ a &H?K#!H?

,atient =it is M2 !)' less eA,ensi9e than a &H?K#7H =it"

The interactions of rifam,icin ith antiretro9iral thera,y 5*?T8 are of concern"2itching to the 7-month rifam,icin regimen means that these drug interactionsmust be ta=en into account for the full 7 months rather than for Eust the 6rst & months

of thera,y" Hoe9er+ the 7-month rifam,icin regimen has mar=ed bene6ts for ,er-sons li9ing ith H0 5see Iuestion ! belo8+ and the drug interactions can be man-

aged 5see section /"7")8" $oreo9er+ *?T is often initiated during the 6rst & months of T% thera,y hen treatment regimens include rifam,icin"

0t as assumed that all ,atients ,refer a regimen that sa9es li9es"

conclusion

?ecommendations )") and )"& ,lace high 9alue on sa9ing li9es" Gi9en both the high@uality of e9idence for this bene6t and the fact that the ,otential harm of ac@uired

$D? can be mitigated by su,er9ision of treatment 5and ,ossibly ith a modi6ed

regimen for ne ,atients in areas ith high le9els of isonia1id resistance8+ these areboth strong recommendations" Periodic drug resistance sur9eys 5or ongoing sur9eil-

lance8 in each country are essential for monitoring the im,act of the regimen and theo9erall treatment ,rogramme"








uestion 2. !re0uency o! dosing in ne/ *atients

When a country selects &H?K#!H?+ should ,atients be treated daily or three timesee=ly during the intensi9e ,hase

Summary of evidence

* systematic re9ie and meta-analysis included &) !3& ,artici,ants in )& arms of /3randomi1ed controlled trials 5?CTs8 conducted in 9arious regions of the orld since



11,


)(7/ 5)8"0n a multi9ariate regression analysis+ each arm of the /3 ?CTs as treated asa se,arate cohort+ and results ere adEusted for ,otentially confounding ,atient andtreatment factors" Only one study of && ,atients e9aluated a rifam,icin-containingregimen administered tice ee=ly throughout thera,y< this study as not included

in the meta-analyses"

Bene0ts and harms of intermittent dosing

.o signi6cant increase in failure+ rela,se or ac@uired drug resistance as found hendaily dosing throughout thera,y as com,ared ith the folloing intermittent regi-

mens in ne T% ,atients o9erall:

daily then three times ee=ly<

daily then tice ee=ly< or three times ee=ly throughout thera,y"

Hoe9er+ the regression analysis shoed that ,atients being treated three times ee=lythroughout thera,y rates of ac@uired drug resistance that ere " times higher than

those in ,atients ho recei9ed daily drug administration throughout treatment"

The meta-analysis re9ealed no dierence in rates of failure+ rela,se or ac@uired drugresistance in ,an-susce,tible ne ,atients being treated ith these dosing schedules"

Hoe9er+ use of a three times ee=ly intensi9e ,hase schedule in ,atients ith ,re-

treatment isonia1id resistance as associated ith a signi6cantly higher ris= of fail-ure and ac@uired drug resistance in another meta-analysis 5see Iuestion 8"


When based in a health facility+ daily administration of thera,y ,laces a larger burdenon T% ,rogrammes and ,atients than intermittent thera,y" 0ntermittent regimens re-@uire stronger ,rogrammes ith higher @uality ,atient su,er9ision+ but all regimens

should be ,ro9ided ith full ,atient su,er9ision and su,,ort 5see Cha,ter 78"

2tudies of ,atientsB ,references for dosing schedules ere not systematically re-9ieed"

The higher isonia1id dose used in intermittent thera,y as not considered to ha9ean increased incidence of ad9erse eects" 5The rifam,icin dosage is unchanged hen

using intermittent thera,y"8

0n an international+ multicentre+ randomi1ed trial 5Mnion 2tudy *8+ indani+ .unn^ narson found three times ee=ly dosing resulted in signi6cantly loer culture

con9ersion rates at & months 5&8"0n de9elo,ing recommendations+ this end-,oint as

ran=ed as im,ortant but not critical for decision-ma=ing 5*nneA 8+ and as not ,artof the systematic re9ie"



119

conclusion

For ne ,atients ithout H0 infection+ high-@uality e9idence demonstrated no sig-ni6cant dierence in regimens that ere administered daily throughout+ daily ini-

tially then intermittently in the continuation ,hase+ or three times ee=ly throughouttreatment"

Daily dosing is o,timal because it ,robably achie9es better adherence under ,ro-)

gramme conditions" 0n addition+ meta-analyses shoed the su,eriority of daily5com,ared ith three times ee=ly8 intensi9e-,hase dosing for ,atients ith ,re-treatment isonia1id resistance and for ,re9enting ac@uired drug resistance in ,a-

tients o9erall"

Gi9en the abo9e considerations of these schedules+ ?ecommendation & for daily dos-

ing throughout thera,y is strong< three times ee=ly intermittent regimens+ hichere found to be e@ually eScacious+ are listed as alternati9es to daily treatment&

throughout thera,y"

There are insuScient data to su,,ort the use of regimens that are gi9en tice ee=lythroughout thera,y" On o,erational grounds+ tice ee=ly dosing is not recom-

mended since missing one dose means the ,atient recei9es only half the regimen" Therecommendation against the use of this regimen is therefore rated as strong"


Where!er #easi)le* the optimal dosing #re+uency #or new patients with pulmo,nary T is daily throughout the course o# therapy




New patients with pulmonary T may recei!e a daily intensi!e phase #ol,

lowed )y three times weely continuation phase /2HR%&'(HR * pro!ided3

that each dose is directly o)ser!ed5Conditional#High or moderate grade of e9idence88


Three times weely dosing throughout therapy /2HR%& '(HR * pro!id,3 3

ed that e!ery dose is directly o)ser!ed therapy and the patient is NOT li!ing

with H45 or li!ing in an H45,pre!alent setting


)While the de6nition of the term 9aries across countries+ dailyQ is considered to mean at least 69etimes ,er ee="

& Three times ,er ee= regimens are deli9ered in a 9ariety of schedules across countries"




12-






uestion 3. Initia# regimen in countries /ith high #eve#s o!

isoniaid resistance

0n countries ith high le9els of isonia1id resistance in ne T% ,atients+ should thecontinuation ,hase 5containing isonia1id and rifam,icin8 be changed in the stand-

ard treatment of all ne ,atients+ in order to ,re9ent the de9elo,ment of multidrugresistance 5This @uestion a,,lies to countries here isonia1id susce,tibility testing

in ne ,atients is not done or results are not a9ailable before the continuation,hase begins"8

Summary of evidence

The systematic re9ie described in Iuestions ) and & re9ealed that+ hen recei9ing aregimen including /R3 months of rifam,icin+ ,atients ith ,retreatment isonia1id re-

sistance 5but susce,tibility to rifam,icin and stre,tomycin8 ere && times more li=elyto ac@uire drug resistance than ,atients ho started treatment ith drug-susce,tible

disease 5)8"

* systematic re9ie and meta-analysis as conducted of trials in9ol9ing )('3ne and ,re9iously treated ,atients ith isonia1id monoresistance" The use of at)

least three eecti9e drugs during the continuation ,hase as associated ith a sig-ni6cantly loer ris= of failure+ and the use of four or more eecti9e drugs during

the intensi9e ,hase as associated ith a signi6cantly loer ris= of failure+ rela,seand ac@uired drug resistance" The use of a daily intensi9e ,hase as associated itha signi6cantly loer ris= of failure and ac@uired drug resistance" The use of stre,-

tomycin as associated ith a signi6cantly loer ris= of failure and ac@uired drug

resistance" The ris= of rela,se as signi6cantly loer ith the use of 7 months of rifam,icin com,ared ith & months+ and / months of ,yra1inamide com,ared ith

no ,yra1inamide"

Bene0ts and harms of adding ethambutol to the continuation phase

The addition of ethambutol as considered as an inter9ention to a9oid hat ould+in eect+ be monothera,y in the continuation ,hase of ne ,atients ith isonia1id

resistance 58"2ur9eillance data sho that only '"7V of ne ,atients ha9e resistance

to both ethambutol and isonia1id+ indicating that the regimen has ,otential eScacy5!8"

) $anuscri,t as submitted+ but not ,ublished at the time of ,ublication of this document" G?*Dtables are a9ailable from WHO u,on re@uest"



121

* fe ,otential harms are associated ith the addition of ethambutol to the con-tinuation ,hase of rifam,icin and isonia1id" 0n countries here the le9el of isonia1id

resistance in ne ,atients e@uals the global eighted mean of 3"!V+ 3! T% ,atients,er )''' ill ha9e isonia1id resistance" This means that for e9ery )''' ne T% ,a-tients+ (&7 ,atients ith isonia1id-susce,tible T% ill recei9e ethambutol unneces-

sarily in order to treat the 3! ith isonia1id resistance" The ris= of ocular toAicity dueto ethambutol as not systematically re9ieed for this edition"

While ides,read use of ethambutol could increase the ris= of ac@uired ethambutolresistance+ ethambutol is not as critical as the inEectables or [uoro@uinolones for the

treatment of $D?-T%" The ac@uisition of ethambutol resistance is less harmful thanthe ac@uisition of resistance to the to classes of drugs that form the bac=boneof $D?-T% regimens" Hoe9er+ loss of a less toAic drug 5if the $D? strain retains sus-

ce,tibility8 may Eeo,ardi1e the ability to cure $D?-T%"


The eAistence of a 6Aed-dose combination of isonia1id+ ethambutol and rifam,icinma=es the addition of ethambutol o,erationally feasible" Countries can use their

drug resistance sur9ey data in ne ,atients to determine hether the le9el of isoni-a1id resistance in ne ,atients arrants the addition of ethambutol" Hoe9er+ about)

/'V of countries 5including four high-burden countries8 ha9e no drug resistance sur-

9eillance data+ e9en at a subnational le9el 5!8"&

2e9eral alternati9es to ethambutol ere considered+ but reEected+ as means to ,rotectrifam,icinQ in ,atients ith ,re-treatment isonia1id resistance:

Xe meXa-analysis shoed XhaX XreaXmenX for / or more monXhs iXh ,yra1in-amide is associated ith a signi6cant decrease in rela,se but is not associated ith

a loer ris= of ac@uired drug resistance" *lthough data on ad9erse eects erenot systematically re9ieed+ ,yra1inamide can cause he,atotoAicity 5,articularlyhen administered ith antiretro9iral thera,y8" Pyra1inamide-associated Eoint

,ain can lead to ,oor adherence"XWhile li=ely Xo be eecXi9e in ,re9enXing ac@uired drug resisXance+ Xhe use of a

[uoro@uinolone in the continuation ,hase for all ne ,atients ould Eeo,ardi1ethis critical class of drugs for $D?-T% ,atients"

X* s,uXum smear obXained aer Xhe second monXh of XreaXmenX is noX hel,ful fordetecting ,retreatment isonia1id resistance 5Iuestion /8"

) *nneA ) 5," )&)8 of the !th WHO#0M*TLD *nti-T% Drug ?esistance ProEect dis,lays each countrys most recent drug resistance sur9ey results in ne ,atients" To determine the le9el of any isonia1id

resistance 5eAcluding $D?8+ countries ill need to do the folloing calculation: V any isonia1id re-sistance 5column )&8 minus V $D? 5column '8" This anneA is a9ailable at: "ho"int#tb#featuresY

archi9e#drsre,ortYlaunchY&7feb'4#en#indeA"html"&2am,le si1es in WHO-s,onsored drug resistance sur9eys are suSciently large to allo ,recise

countryide estimates+ but not estimates for subregions or ,o,ulations 5unless they ere s,eci6callysam,led8"




122


conclusion

This recommendation ,laces a high 9alue on ,re9enting the de9elo,ment of $D?in areas here isonia1id resistance is ,re9alent among ne cases and isonia1id sus-

ce,tibility testing in ne ,atients is not done 5or results are not a9ailable8 beforethe continuation ,hase begins" 0t is a conditional recommendation for the folloingreasons"

The most eecti9e regimen for the treatment of isonia1id-resistant T% is not =non" There is inade@uate e9idence to @uantify the ability of ethambutol to ,rotectrifam,icinQ in ,atients ith ,re-treatment isonia1id resistance" There is a ris= of ,er-

manent blindness+ although e9idence for ocular toAicity from ethambutol as notsystematically re9ieed for this edition"

Further research 5see *nneA /8 is thus needed to de6ne the le9el of isonia1id resistancethat ould arrant the addition of ethambutol 5or other drugs8 to the continuation,hase of the standard regimen for ne ,atients in T% ,rogrammes here isonia1id

susce,tibility testing in ne ,atients is not done 5or results are not a9ailable8 beforethe continuation ,hase begins"

2ee also Iuestion &: 0n ,atients ith ,retreatment isonia1id resistance+ daily dosingduring the intensi9e ,hase as associated ith signi6cantly loer ris=s of failure andac@uired drug resistance than three times ee=ly dosing during the intensi9e ,hase"

L Recommendation 34n populations with nown or suspected high le!els o# isoniazid resistance* new

T patients may recei!e HR& as therapy in the continuation phase as an accept,



uestion %. " treatment in *ersons #iving /ith 'I(

2hould intermittent regimens be used for ,ersons li9ing ith H0 What should be

the duration of T% treatment in ,eo,le li9ing ith H0

Summary of evidence

* systematic re9ie and meta-analysis of 7 randomi1ed controlled trials and & co-hort studies ,ro9ided ,ooled estimates of failure+ rela,se and death by duration of

rifam,icin+ and daily intensi9e ,hase 9s intermittent throughout 5/8" The systematicre9ie re9ealed a mar=ed and signi6cant reduction in failure and rela,se in the arms

here some or all ,atients recei9ed *?T"



123

Bene0ts and harms of intermittent intensive phase! and of e%tending

the duration of therapy

0n a regression model+ treatment failure or rela,se as )"4&"/ times more li=ely ith

intermittent rather than daily dosing in the intensi9e ,hase"Com,ared ith 4 or more months of rifam,icin+ &-month rifam,icin regimens car-

ried a -fold higher ris= of rela,se and 7-month regimens a &"& -fold higher ris="

other considerations and conclusions

%ecause most of the data in the systematic re9ie are from cohort studies+ the data@uality is considered lo" .onetheless+ daily dosing during the intensi9e ,hase is a

strong recommendation for ,eo,le li9ing ith H0 for the folloing reasons:

Xe in9esXmenX in changing from inXermiXXenX Xo daily Xhera,y during Xhe inXen-si9e ,hase re,resents a ise use of resources gi9en the ,otential bene6t"

XPaXienXs are assumed Xo ,refer a regimen iXh loer failure and rela,se+ e9en if they ha9e to come to a health facility for daily dosing"

The meta-analysis of T% ,atients li9ing ith H0 contained no data com,aring adaily ith a three times ee=ly continuation ,hase" For this reason+ and for consist-

ency ith ?ecommendation &")+ ?ecommendations !"& and !" are conditional"

Atending treatment beyond 7 months is recommended by some eA,ert grou,s incertain ,ersons li9ing ith H0 578 and the meta-analysis shoed that this is associ-ated ith signi6cantly loer rela,se rates 5/8" Hoe9er+ se9eral other considerations

are gi9en greater eight" 2e,arate regimens for T% ,atients li9ing ith or ithoutH0 ould be o,erationally 9ery challenging and could add stigma" Other ,otential

harms of eAtending treatment are ac@uired rifam,icin resistance+ and a longer ,eriodduring hich antiretro9iral thera,y o,tions are limited 5because of *?Trifam,icin

interactions8"

L Recommendation (.1T patients with nown positi!e H45 status and all T patients li!ing in H45,

pre!alent settings should recei!e daily T treatment at least during the inten,1

si!e phase




patients


)H0-,re9alent settings are de6ned as countries+ subnational administrati9e units+ or selected facilitieshere the H0 ,re9alence among adult ,regnant omen is U)V or H0 ,re9alence among T% ,atients

is U/V 538"




12%




5Conditional#High or moderate grade of e9idence8L Recommendation (.(

4t is recommended that T patients who are li!ing with H45 recei!e the same

duration o# T treatment as H45,negati!e T patients


uestion 5. S*utum monitoring during " treatment o! smear&*ositive

*u#monary " *atients

0n ,ulmonary T% ,atients ho are initially smear-,ositi9e+ ho eecti9e are s,utums,ecimens for ,redicting rela,se+ failure and ,retreatment isonia1id resistance

Summary of 0ndings

To determine the ability of s,utum smears at months & or of treatment to ,redictrela,se+ results of randomi1ed controlled trials conducted by the %ritish $edical

?esearch Council 5$?C8 in9ol9ing a,,roAimately )('' ,atients from the )(3's and4's across *sia and east *frica ere reanalysed" *ll ,atients recei9ed a 7-month)

regimen ith at least four drugs in the initial & months" The sensiti9ity of the smearat either month & or month in identifying ,atients ho ill rela,se is less than !'V<less than one-@uarter of the ,atients ith ,ositi9e smears ill rela,se 5assuming a 3V

rela,se rate8"

* se,arate systematic re9ie also found that s,utum smear at month & or of treat-&

ment has limited utility in ,redicting rela,se" For e9aluating a diagnostic test 538+ the$?C reanalysis and the systematic re9ie are considered moderate- and lo-@uality

e9idence+ res,ecti9ely"

0t is not ,ossible to determine the ability of the smear to ,redict failure for the fol-loing reasons:

X0n Xhe $?C Xrials+ Xhere ere fe XreaXmenX failures obser9ed and iX as Xhereforeim,ossible to carry out a meaningful analysis"

X0n Xhe sysXemaXic re9ie+ Xhe @ualiXy of e9idence in mosX sXudies XhaX assessed fail-ure is 9ery lo"

) The original ,ublished results from these studies ere based on analyses using ,er-,rotocol ,o,ula-tions" The reanalysis as based on indi9idual ,atient+ intention-to-treat data" *ll cultures ere done

on solid media"&$anuscri,t as not ,ublished at the time of ,ublication of this document" G?*D tables are a9ailable

from WHO u,on re@uest"



125

Bene0ts and harms of obtaining a smear at ) months and! if positive!

obtaining culture and dST

The main rationale for recommending the addition of a -month s,utum smear is to

detect ,oor res,onse to thera,y earlier than the 6fth month 5the current algorithm8"High 9alue as ,laced on the need to detect $D? as soon as ,ossible+ e9en thoughthe $?C reanalysis shoed that smear or culture results at month )+ &+ or ! are not

,redicti9e of ,retreatment isonia1id resistance" 5The $?C studies ere done beforethe emergence of rifam,icin resistance and are therefore not directly rele9ant to the

ability of s,utum monitoring to detect $D?-T%"8

The alternati9e of using the &-month smear for triggering a culture as also consid-ered" The ad9antage ould be earlier detection of $D?-T% 5since most ill ha9e had

no D2T at the start of thera,y8" Hoe9er+ there are ,rogrammatic bene6ts from usingthe -month 5rather than the &-month8 smear as a trigger for culture and D2T" Fore9ery )''' T% ,atients ho are smear-,ositi9e at the start of treatment+ )4 are eA-

,ected to remain smear-,ositi9e at & months and only 4 at months" %y inter9eningith culture and D2T on the basis of the -month+ rather than the &-month+ s,utum

smear result+ national T% ,rogrammes ill ha9e )'' feer ,atients needing thesemore com,leA laboratory tests for e9ery )''' T% ,atients ho start thera,y"

other considerations and conclusion

These recommendations retain the original ,ur,ose of s,utum monitoring+ hichas to assess ,rogramme ,erformance" High 9alue is ,laced on the need to detect

treatment failure due to $D?-T% earlier in the course of treatment than the 6fthmonth 5as ,er the ,re9ious WHO algorithm8" Gi9en the moderate to lo @uality of

e9idence and o,erational concerns arising from the ,oor ability of the smear to ,re-dict rela,se+ this is a conditional recommendation"


7or smear,positi!e pulmonary T patients treated with 9rst,line drugs*

spu,tum smear microscopy may )e per#ormed at completion o# the intensi!e phaseo# treatment



4n new patients* i# the specimen o)tained at the end o# the intensi!ephasemonth 2 is smear,positi!e* sputum smear microscopy should optimally

)e o)tained at the end o# the month 3





12)




52trong#High grade of e9idence8L Recommendation 8.(

4n pre!iously treated patients* i# the specimen o)tained at the end o# the inten,

si!e phase month 3 is smear,positi!e* sputum culture and drug suscepti)ility



uestion ). reatment extension in ne/ *u#monary " *atients

0n ne ,ulmonary T% ,atients+ ho eecti9e is eAtension of treatment for ,re9entingfailure or rela,se

Summary of 0ndings

The systematic re9ie identi6ed only one rele9ant study" * study currently under ay)

in %angladesh of a 7-month rifam,icin-containing regimen randomi1ed 33/ nesmear-,ositi9e ,atients ho remained ,ositi9e at & months to either the )-month eA-tension arm 5eAtension of the intensi9e ,hase by ) month8 or the no-eAtension arm"

Bene0ts and ris&s of e%tending treatment for patients who are

smear$positive at 2 months

Preliminary results at ) year of follo-u, shoed that ,atients in the )-month eAten-sion arm had a signi6cantly loer rela,se rate 5relati9e ris= '"3+ (/V C0 '"&)+ '"778

than ,atients in the no-eAtension arm" * smaller decrease in failure in the )-montheAtension arm as not statistically signi6cant" Gi9en the ,reliminary nature of the

results and ,assi9e follo u, of ,atients+ the e9idence from the %angladesh study as

graded moderate @uality"0n )''' T% ,atients ith a 3V ris= of rela,se+ the %angladesh study ,redicts that

eAtending the treatment of )4 ,atients ho are smear-,ositi9e at & months oulda9ert )7 of the 3' eA,ected rela,ses" Hoe9er+ to achie9e this &V reduction in re-&

la,ses+ )/4 ,atients ,er )''' ould be incorrectly ,redicted to rela,se< their treat-ment ould be eAtended unnecessarily"

) G?*D tables are a9ailable from WHO u,on re@uest"&stimates from Iuestion / shos that the &-month smear ill correctly identify &/ ,atients ho ill

rela,se after treatment and incorrectly identify )/4 ,atients ho ill not rela,se8 0f the intensi9e ,haseis eAtended for these &/ ,atients hose ,ositi9e smear at & months correctly ,redicts that they ill

rela,se+ the %angladesh study ,redicts that they ill ha9e a 3V reduction in rela,se" 0nstead of all &/rela,sing+ only ( ,er )''' ould rela,se 5'"3 A &/8< that is+ )7 rela,ses ould be ,re9ented" Hence+instead of the 3' eA,ected rela,ses in the cohort of )'''+ obtaining s,utum smears at & months and

eAtending treatment for those ho are smear-,ositi9e ould result in /! rela,ses+ a &V reduction"



12+

other considerations and conclusion

While eAtending rifam,icin beyond 7 months reduces the ris= of rela,se+ there is)

insuScient e9idence to determine hich ,atients are most li=ely to bene6t" Histori-

cally+ hen the ne ,atient regimen included only & months of rifam,icin+ the eA-tension of the intensi9e ,hase meant an eAtra month of su,er9ised rifam,icin" ThiseAtra month is less im,ortant no+ hen the recommended regimen is 7 months of su,er9ised rifam,icin" Gi9en these considerations+ together ith ,reliminary results

from one moderate-@uality study that shoed only modest bene6t+ a conditional rec-ommendation as made not to eAtend treatment on the basis of a ,ositi9e smear at

& months"

L Recommendation "

4n patients treated with the regimen containing ri#ampicin throughout treat,

ment* i# a positi!e sputum smear is #ound at completion o# the intensi!e phase*

e6tension o# the intensi!e phase is not recommended


uestion +. revious#y treated *atients

Which 5if any8 grou,s of ,atients should recei9e a retreatment regimen ith 6rst-linedrugs

Summary of 0ndings

The systematic re9ie found no randomi1ed controlled trial of the 4-month retreat-ment regimen ith 6rst-line drugs" 2iA cohort studies of this regimen in ,re9iously

treated ,atients included 4(4 ith ,an-susce,tible strains and )&! ith isonia1idmonoresistance" Failure rates ranged from )V to &3V in ,atients ith ,an-susce,ti-

ble disease and from )4V to !!V in those ith isonia1id monoresistance 548"

0n de9elo,ing recommendations+ the retreatment regimen of 6rst-line drugs as

considered only for em,irical thera,y+ hile aaiting D2T results+ ,re9iously treated,atients at medium to lo li=elihood of $D?" Hoe9er+ the recommendations are&

not rated since the @uality of e9idence as not e9aluated according to G?*D meth-odology"

) The head-to-head com,arison described in Iuestion ) shoed a !V dierence beteen the ,ro,or-tion rela,sing after 7 months of rifam,icin-containing treatment and the ,ro,ortion rela,sing after (

months of rifam,icin-containing treatment"&Countries that ado,t ra,id D2T 5such as the line ,robe assay8 ill be able to con6rm or eAclude $D?

ithin hours to days" This allos the results to guide the choice of regimen right at the start of treat-ment" These countries do not need the retreatment regimen ith 6rst-line drugs" Countries using

con9entional D2T ill need an em,irical $D? regimen for ,re9iously treated ,atients ith a highli=elihood of ha9ing $D?+ hile aaiting D2T results" For those ith a medium or lo li=elihood of

ha9ing $D?-T%+ the bene6ts and harms of using of the 4-month retreatment regimen ith 6rst-linedrugs 5hile aaiting D2T results8 are as discussed in the teAt"




12,


Bene0ts and harms of using a retreatment regimen with 0rst$line drugs for patients

with low to medium li&elihood of having mdr

For retreatment of ,atients ho do not ha9e $D?+ the 6rst-line drug retreatment

regimen a9oids eA,osure to a ,rolonged regimen of toAic second-line drugs" Otherbene6ts for non-$D? ,atients are sa9ings in ,atient time and resources and+ ,rob-ably+ a diminished ris= of defaulting" %y using only 6rst-line drugs+ the WHO re-treatment regimen conser9es ,rogramme resources and ,reser9es the acti9ity of

[uoro@uinolones and inEectables 5ami=acin and =anamycin8 for ,atients ho trulyneed these drugs 5i"e" those ith documented $D?8"

On a global le9el+ 7/V of ,re9iously treated ,atients ha9e$" tuberculosisorganismsthat are still fully susce,tible 5!8" For these ,atients+ the 6rst-line retreatment regi-

men ,ro9ides the bene6t of the to best anti-T% drugs+ isonia1id and rifam,icin" Forthe )&"!V of ,re9iously treated ,atients at the global le9el hose$" tuberculosisisisonia1id-resistant but not $D?+ the retreatment regimen of 6rst-line drugs is of un-

,ro9en eScacy< hoe9er+ the data in Iuestion suggest that the use of stre,tomycin+a daily intensi9e ,hase+ and four eecti9e drugs in the intensi9e ,hase may im,ro9e

outcomes"

The main harm of the 4-month retreatment regimen ith 6rst-line drugs is that ,re-9iously treated ,atients hodoha9e $D? 5)/"V at the global le9el8 ill recei9e

inade@uate treatment during the ee=s to months of aiting for D2T results" Patients

may become more ill and asted+ s,read $D?-T% to others+ and see= care from ,ro-9iders not lin=ed to the .TP ho may not follo .TP treatment guidelines" Mse of

the retreatment 6rst-line drug regimen in $D? ,atients may also result in ac@uiredethambutol resistance"


For retreatment ,atients at medium to lo li=elihood of $D?+ the folloing alterna-ti9es to the 6rst-line drug retreatment regimen ere considered and reEected:

X7H?K may be eecXi9e againsX isonia1id-resisXanX$" tuberculosis5see Iuestion8+ but toAicity is a concern hen ,yra1inamide is used throughout thera,y"

X&H?K#!H? is recommended for use in ne ,aXienXs iXh high le9els of iso-nia1id resistance 5see Iuestion 8+ but )'"V of ,re9iously treated ,atients ha9e

ethambutol resistance 5com,ared ith &"/V of ne ,atients8 5!8+ hich ould ren-der this regimen less eecti9e"

XOmission of sXre,Xomycin from Xhe reXreaXmenX regimen as reEecXed gi9en XhaXthis inEectable may strengthen this regimen 5see Iuestion 8 and does not com,ro-

mise ami=acin or =anamycin for use in $D? ,atients"

XMsing Xhe same 7-monXh regimen as is used for ne ,aXienXs as also reEecXed" Forthe )/"V of ,re9iously treated ,atients ho do ha9e $D?+ the !-month isonia1id



129

and rifam,icin continuation ,hase ould theoretically not Eeo,ardi1e ethambutolto the same eAtent as the 4-month regimen ith its /H? continuation ,hase"

For the )&"!V of ,re9iously treated ,atients ho ha9e isonia1id resistance but not$D?+ the isonia1id and rifam,icin continuation ,hase could lead to ac@uired

$D?" Thus the ,ossible bene6t of using the ne ,atient regimen to ,reser9eethambutol in $D? ,atients is ,robably outeighed by the ris= of ac@uiring ri-

fam,icin resistance in the scenario of ,re-eAisting isonia1id resistance"

Xe o,Xion of augmenXing Xhe 4-monXh reXreaXmenX regimen iXh a uoro@uinolo-ne or an inEectable other than stre,tomycin as reEected in order to ,reser9e these

to classes of drugs+ hich form the bac=bone of $D?-T% treatment"

conclusion

When com,ared ith the alternati9e of ,ro9iding an $D? regimen to all ,re9i-ously treated ,atients+ the ris=s 5toAicity+ cost and de9elo,ment of resistance to im-,ortant $D? drugs8 outeigh the bene6ts" There as no other alternati9e found to

the 4-month retreatment regimen ith 6rst-line drugs" 2ince the e9idence for thisregimen is of 9ery lo @uality+ this is a conditional recommendation"


;pecimens #or culture and drug suscepti)ility testing :;T should )e o)tained

#rom all pre!iously treated T patients at or )e#ore the start o# treatment. :;T



4n settings where rapid :;T is a!aila)le* the results should guide the choice o#

regimen


4n settings where rapid :;T results are not routinely a!aila)le to guidethemanagement o# indi!idual patients* empirical treatment should )e started as

#ollows$


T patients whose treatment hasfailedor other patient groups with high

lielihood o# multidrug,resistant T =:R should )e started on an empiri,

cal =:R regimen


T patients returning a#ter de#aulting or relapsing #rom their 9rst treat,


2HR%&;'1HR%&'8HR& i# country,speci9c data show low or medium le!elso# =:R in these patients or i# such data are una!aila)le




13-







National T control programmes NT?s should o)tain and use their country,

speci9c drug resistance data on #ailure* relapse and de#ault patientgroups todetermine the le!els o# =:R

re!erences

$en1ies D et al" ect of duration and intermittency of rifam,in on tuberculosis)"treatment outcomes a systematic re9ie and meta-analysis"Plo2 $edicine+ &''(+7:e)''')!7"

indani *+ .unn *+ narson D*" To 4-month regimens of chemothera,y for treat-&"ment of nely diagnosed ,ulmonary tuberculosis: international multicentre ran-

domised trial"Lancet+ &''!+ 7!:)&!!)&/)"$itchison D*" %asic mechanisms of chemothera,y"" Chest+ )(3(+ 3757 2u,,l"8: 33)34)"*nti-tuberculosis drug resistance in the orld: fourth global re,ort!" " Gene9a+ WorldHealth Organi1ation+ &''4 5WHO#HT$#T%#&''4"(!8"

Nhan F* et al" Treatment of acti9e tuberculosis in H0 co-infected ,atients: a sys-/"

tematic re9ie and meta-analysis"Clinical 0nfectious Diseases+ &')' 5in ,ress8"*merican Thoracic 2ociety+ CDC+ 0nfectious Diseases 2ociety of *merica" Treat-7"

ment of tuberculosis"$orbidity and $ortality Wee=ly ?e,ort: ?ecommendations and?e,orts+ &''+ /&5??-))8:)33"

2chnemann H et al" Grading @uality of e9idence and strength of recommendations3"for diagnostic tests and strategies"%ritish $edical ournal+ &''4+ 7:))'7)))'"

$en1ies D et al" 2tandardi1ed treatment of acti9e tuberculosis in ,re9iously treated4",atients+ and#or ith mono-resistance to isonia1id a systematic re9ie and meta-

analysis"Plo2 $edicine+ &''(+ 7:e)''')/'"



131

a3

T% treatment outcomes

For the meeting in October &''4+ members of the Guidelines Grou, scored the T%treatment outcomes that they considered to be the most critical for the choice of T%

treatment regimens" They ere as=ed to ta=e the ,oint of 9ie of .TP managers thetarget audience for this ,ublication" Of the )( members ho attended that meeting+

)/ 53(V8 res,onded< the results are shon belo"

2core ?elati9e im,ortance) .ot im,ortant for ma=ing recommendations on T% regimen!7 0m,ortant but not critical for ma=ing recommendations on T% regimen3( Critical for ma=ing recommendations on T% regimen

what are the most important bene*cial outcomes to consider when ma&ing

decisions on TB treatment regimensN

outcomesre#ative

im*ortance

reducing emergence of mdr$TB! prevent drug resistance

Survival

Staying disease$free "avoiding relapse#

Halting transmission of TB! a TB$free community

Bacteriological cure

negative sputum smears at 2 months

relief of TB symptoms

cost savings

9

9

9

9

7

7

*

*

what are the most signi0cant riss to consider when ma&ing decisions on

TB treatment regimensN

outcomesre#ative

im*ortance

Acquired drug resistance

failure

relapse

infecting health care wor&ers and the community

default

loss of ef0cacy of Hi' medicines due to poorly managed drug interactionsdrug to%icity

interaction with non$TB medications

financial burden

9

9

9

;

;

;;

7

*



133

a%

im,lementation and e9aluationof the fourth edition

* strategy for eecti9e u,ta=e re@uires de6nition of the =ey messages+ the audiencesand the actions for them to ta=e" The =ey messages of this fourth edition are the eight

strong recommendations listed in Table *!")" %y designating them as strongQ+ theGuidelines Grou, is con6dent that their im,lementation ill yield signi6cant health

bene6ts+ outeighing any ,otential harms")

Table A4(- STrong recommendATionS

no. recommendation

ne/ *atients

-(-

-(2

replace 7He in the continuation phase with 4Hr

2(- implement daily treatment throughout the course of therapy

2(4 discontinue regimens using twice wee&ly dosing throughout therapy

'I(&*ositive " *atients= /hether their " is ne/ or *revious#y treated

4(-

4(2

TB patients living with Hi'! and all patients living in Hi'$prevalent settings!

should receive daily TB treatment at least during the intensive phase

"optimally! also in the continuation phase#

4(4 for TB patients living with Hi'! implement at least the same duration of daily

treatment as for Hi'$negative patients

S*utum monitoring during " treatment 8ne/ and *revious#y treated

*(2 perform additional sputum e%amination at month ) if sputum smear is positive

at month 2 "in new patients#

*()

*(4

obtain specimen for culture and dST if sputum smear$positive at month ) "in

new and previously treated patients#

reatment extension

7 no need for e%tending the intensive phase of treatment( That recommendation

will require changes in training and drug supply systems

Ney audiences for these recommendations are members of international T% organi-1ations+ WHO regional oSces+ and national T% control ,rogrammes 5es,ecially in

countries ith high T% burdens+ high le9els of $D?-T% and#or T%#H08" Targetaudiences ithin countries include other T% ser9ice ,ro9iders or=ing in ,ublic and

)%ecause the rest of the recommendations are conditional+ they are loer ,riority for im,lementationand e9aluation"



13 %


,ri9ate health care facilities at the central and ,eri,heral le9els 5see section )"8" Theactions for all the target audiences are to im,lement these eight recommendations in

the conteAt of their o9erall T% ,riorities"

$onitoring and e9aluation should be built into im,lementation+ in order to ,ro9ideim,ortant lessons for u,ta=e and continued im,lementation 5)8" 0n the frameor=,resented in Table *!"&+ these eight strong recommendations arein,utsthat shouldim,ro9e the,rocessesof T% treatment and re,orting+ hich in turn should im,ro9etheoutcomesof treatment success and reduced drug resistance+ and 6nally ha9e anim,act on reducing T% ,re9alence+ incidence and death"

Table A4(2 frAmewor, for e'AluATing THe impAcT of THe fourTH ediTion a

Indicator ty*es Indicators

input Activities "such as nTp manual revised to adopt new recommendations#

process improve TB management "such as proportion of previously treated

patients with culture and dST performed on sputum specimens at the

start of therapy#

outcome improve treatment success "such as proportion of previously treated

patients who are cured#

impact reduce TB prevalence! incidence and death "mdg 7#

reduce poverty "mdg -# b

a Adapted from+ $O'+ 56#ansion Woring rou# +trategic lan 200720)9( geneva! world Health orga$

niation! 2887 "wHo1HTm1TBN2887();8#! p( 7(b mdg = millennium development goal(

necessary ste*s !or im*#ementation o! s*ecific recommendations>

corres*onding eva#uation indicators

The necessary ste,s 5,rere@uisites8 for im,lementing each recommendation are listed

belo" For all eight recommendations+ information on the folloing outcome andim,act indicators is already routinely collected 5or estimated8:

XOuXcome indicaXors: cure+ XreaXmenX success+ defaulX 5recording and re,orXingforms+ WHOBs annualGlobal tuberculosis controlre,ort8+ le9el of drug resistance5drug resistance sur9eys8"

X0m,act indicators: T% incidence and mortality 5WHOBsGlobal tuberculosis controlre,ort 5&88"

2,eci6c ,rocess indicators for e9aluating each recommendation are listed belo"

recommendation -(-

.e ,atients ith ,ulmonary T% should recei9e a regimen containing 7 monthsBrifam,icin: &H?K#!H?"



135

annEx %. Im#EmEnaIon and E(a#uaIon o! 'E !our'EdIIon

recommendation -(2

The &H?K#7H treatment regimen should be ,hased out"

Prere@uisites:

X0n counXries XhaX ha9e been using a self-adminisXered conXinuaXion ,hase+ eA,andsu,er9ised treatment to allo rifam,icin to be gi9en safely throughout thera,y"

Process indicators for e9aluation 5WHOBsGlobal tuberculosis controlre,ort 5&8+ GDFdata8:

number of countries changing to the !-month isonia1id and rifam,icin con-)

tinuation ,hase< number of ne ,atients recei9ing the 7 monthsB rifam,icin regimen<

number of ,atients ith su,er9ised treatment throughout thera,y"

recommendation 2(2

.e ,atients ith T% should not recei9e tice ee=ly dosing for the full course of treatment unless this is done in the conteAt of formal research"

recommendation 4(-

T% ,atients ith =non ,ositi9e H0 status and all T% ,atients li9ing in H0-,re9a-

lent settings should recei9e daily T% treatment at least during the intensi9e ,hase"Prere@uisites:

XA,and XreaXmenX su,er9ision in counXries XhaX ha9e been using Xice ee=lydosing for any T% ,atients+ or three times ee=ly intensi9e-,hase dosing for T%

,atients ho are H0-,ositi9e or li9ing in an H0-,re9alent setting"

Process indicators for e9aluation 5WHOBsGlobal tuberculosis controlre,ort 5&8+Global Drug Facility data8:

number of countries eliminating tice ee=ly dosing schedules< number of countries in hich .TP guidelines change to recommend dailyintensi9e-,hase treatment of H0-,ositi9e T% ,atients<

number of H0-,ositi9e ,atients recei9ing daily intensi9e-,hase treatment"

$#o"a# #eve# actions !or im*#ementation and eva#uation

*t the global le9el+ im,lementation and e9aluation of these eight recommendationsill necessitate:

XWHO and ,arXners assisXing counXries Xo esXablish drug resisXance sur9eys of ne,atients+ and ongoing sur9eillance of D2T of all ,re9iously treated ,atients" Thisill re@uire strengthened laboratory ca,acity"

) Other calculations 5such as ,ro,ortions8 ill also be useful"



13)


XWHO and ,arXners assisXing counXries Xo ensure XreaXmenX su,er9ision Xhrough-out thera,y"

XWHO and ,arXners idenXifying+ and assisXing in Xhe u,daXing of+ eAisXing Xraining

materials and other technical tools 5such as guidance for Global Fund a,,lica-tions+ district and health facility training modules8+ and fostering their u,ta=e and

use"

XWHO u,daXing insXrucXions and forms for recording and re,orXing and assisXingcountries ith im,lementation"

XWHO adEusXing indicaXors 5+!8 to ca,ture the data needed to e9aluate these rec-ommendations 5i"e" ,ro,ortion of failure+ rela,se and default ,atients ith culture

and D2T ,erformed at the start of thera,y8"

Xe Global Drug FaciliXy 5GDF8 re-forecasXing drug needs+ ,ro9iding guidance Xocountries on the transition from old to ne regimens+ and ,ro,osing a ,hase-out

,lan for eAisting stoc=s in ,ublic and ,ri9ate sectors 5/8"

Xe $D?-T% XreaXmenX ,rogrammes scaling u, 5including a9ailabiliXy of @ualiXy-assured second-line drugs8 no that an $D? regimen is recommended as ,art of

each country s standard regimens"

The recommendations in these guidelines su,,ort the Global Plan to 2to, T% 5!8and

the 2to, T% 2trategy 578"0m,lementation of the four recommendations for,re9iouslytreated,atients is already ,art of the ,rogramme of or= of the WHO 2to, T% De-,artment and the $D?-T% Wor=ing Grou, 5$D?-T% WG8 of the 2to, T% Partner-

shi," The other recommendations re,resent changes to standardi1ed treatment underthe DOT2 com,onent of the Global Plan to 2to, T%+ for hich the WHO 2to, T%De,artment in ,artnershi, ith the DOT2 A,ansion Wor=ing Grou, 5DWG8

is res,onsible" The latter includes the Global Laboratory 0nitiati9e 5GL08+ hich is inthe ,rocess of eA,anding ca,acity for culture and D2T" The H0#T% Wor=ing Grou,5T%#H0 WG8 could foster im,lementation of daily intensi9e-,hase dosing for T%

,atients ho are H0-,ositi9e or li9ing in H0-,re9alent settings"* broad grou, of sta=eholders from .TPs+ international organi1ations ,ro9iding T%

technical assistance 5including WHO regional and country oSces8+ members of theWHO 2trategic+ Technical and *d9isory Grou, 52T*G T%8+ and ,atient re,resenta-

ti9es ere engaged as members of the Guidelines Grou, in the de9elo,ment of thisfourth edition 5*nneA 78" The in9ol9ement of these members of the target audience

throughout the de9elo,ment ,rocess should increase buy-in and facilitate im,lemen-tation" 2ynchroni1ation of this re9ision ith u,dates to the0nternational standards

for tuberculosis care538should hel, ,a9e the ay toards ado,tion by ,ri9ate ,racti-tioners or=ing at the country le9el"

WHO and international ,artners can incor,orate these ne recommendations intheir ongoing technical su,,ort and ca,acity-building eorts in countries" Aisting



13+

mechanisms for technical assistance also include T%T*$+ the Green Light Com-mittee 5GLC8 0nitiati9e+ and the GDF" 0nternational ,artners can also hel, countries

to incor,orate these recommendations into their country-s,eci6c T% ,lans and tomobili1e funding from domestic sources or international 6nancing mechanisms

5such as the Global Fund to Fight *0D2+ Tuberculosis and $alaria8" *s the recom-mendations are im,lemented+ e9aluation of a number of indicators is already built in

to routine monitoring of ,rogress toards targets and Global Plan im,lementation"

*dditional global le9el actions could include:

XDe9elo,+ budgeX and im,lemenX a communicaXion and disseminaXion ,lan includ-ing ,resentations at international meetings and or=ing grou, meetings"

XPre,are mulXi,le formaXs 5informaXion ,roducXs8 such as:

,lacing the guidelines on the WHO eb site< translating into oScial WHO languages< summary of recommendations< ,olicy briefs for international and country use< inclusion in WHO Technical ?e,ort 2eries indeAed on $edline 5ith 02%.8"

XPlan for and assisX iXh regional#counXry im,lemenXaXion:

or= ith technical ,artners and ith WHO regional and country oSces

to determine hich recommendations are ,riorities for im,lementation ande9aluation in hich regions< analyse ca,acity of health systems in high-burden countries to ado,t and e9al-

uate the ne recommendations"

regiona# and country #eve# actions

?egions and countries ill need to select the recommendations that ha9e the highest,riority for im,lementation in the conteAt of regional and national T% ,lans+ local

e,idemiology and health systems" For eAam,le+ introduction of li@uid media for cul-ture and D2T should be based on com,rehensi9e country-s,eci6c ,lans for labora-

tory ca,acity-strengthening" * country ith high error rates in smear microsco,yill 6rst strengthen eAternal @uality assurance of microsco,y before introducing cul-ture" 2imilarly+ the recommendations for treatment regimens must be im,lemented

in the conteAt of the country s drug management and su,,ly systems" * countryith fre@uent stoc= outs of 6rst-line drugs ill address this ,roblem before changing

continuation ,hase-drugs to im,lement ?ecommendation )"

*dditional country and regional le9el actions could include:

X TranslaXing Xhe fourXh ediXion inXo a,,ro,riaXe languages as needed"

X9aluaXing sur9eillance daXa Xo XargeX ,arXicular counXries for im,lemenXaXionand e9aluation of s,eci6c recommendations" For eAam,le+ the &''( WHOGlobal




13,


tuberculosis controlre,ort shoed that & countries ere still using the 7H con-tinuation ,hase"

X*ssisXing counXries in securing funding for+ ,lanning+ im,lemenXing and e9aluaX-

ing these recommendations"XCon9ening sXa=eholders 5including ,rofessional associaXions8 Xo:

analyse the need for the change at regional or country le9el and the ris=s andbene6ts of im,lementing the recommendation<

analyse the ca,acity 5,ublic and ,ri9ate sector8 of the region or country toim,lement the change<

identify and @uantify factors that may constrain or facilitate successful im,le-mentation<

de9elo, regional or country ,olicy and obtain endorsement"

XDe9elo, a ,lan for im,lemenXaXion and e9aluaXion+ including:

=ey in,uts and budget< se@uencing of =ey tas=s 5hich may include a feasibility study or demonstra-

tion ,roEects8 and ho the change ill be ,hased in gradually 5or rolled out allat once8<

training of health or=ers and community ,artners+ coordinated ith su,,lyand infrastructure changes<

re9ision of recording and re,orting forms< de9elo,+ 6eld test+ and disseminate an o,erational guide and tool=it to assistcountries and decision-ma=ers to im,lement and e9aluate the ne recommen-

dations"

XDe9elo, a communicaXion ,lan+ including brieng decision-ma=ers in Xhe min-istry of health+ ,rofessional associations+ and donors" nsure consistent messages

are communicated to health care or=ers+ community ,artners ,ro9iding care+and the ,ublic" This could include de9elo,ing a ,oc=et card and all ,oster com-

bining Tables "&+ " and "! 5to re,lace categories 008" 0nclude names for thene ,atientQ+ retreatment ith 6rst-line drugsQ+ and $D?Q regimens to re,lacethe familiar nic=names of the ,re9ious treatment scheme: categories )+ &Q+ etc"

X*ssisX naXional T% conXrol ,rogrammes in u,daXing naXional T% guidelines andmanuals+ laboratory standard o,erating ,rocedures+ T% section of H0 guide-

lines+ drug su,,ly management systems"



139

re!erences

.e technologies for tuberculosis control: a frameor= for their ado,tion+ introduc-)"tion and im,lementation" Gene9a+ World Health Organi1ation+ &''3 5WHO#HT$#

2T%#&''3"!'8"*nti-tuberculosis drug resistance in the orld: fourth global re,ort&" " Gene9a+ WorldHealth Organi1ation+ &''4 5WHO#HT$#T%#&''4"(!8"

$onitoring and e9aluation tool=it: H0#*0D2+ T%+ malaria+ and health systems"strengthening+ rd ed" Gene9a+ The Global Fund to Fight *0D2+ Tuberculosis and$alaria+ &''( 5a9ailable at htt,:##"theglobalfund"org8" The Global Plan to 2to, T%+ &''7&')/!" " Gene9a+ World Health Organi1ation+ &''75WHO#HT$#2T%#&''7"/8"

Com,endium of indicators for monitoring and e9aluating national tuberculosis ,ro-/"grammes" Gene9a+ World Health Organi1ation5 WHO#HT$#T%#&''!"!!< 5a9ail-

able at: htt,:##h@libdoc"ho"int#h@#&''!#WHOYHT$YT%Y&''!"!!",df8"Phanou9ong 2"7" O,erational guide for national tuberculosis control ,rogrammes on theintroduction and use of 6Aed-dose combination drugs"Gene9a+ World Health Organi-1ation+ &''& 5WHO#CD2#T%#&''&"'48"0nternational standards for tuberculosis care3" + &nd ed" The Hague+ Tuberculosis Coali-tion for Technical *ssistance+ &''("




1%1

a5

suggestions for future research

*t many ,oints during the ,rocess of re9ising the third edition+ future research needsere identi6ed" There as often no e9idence a9ailable to allo the formulation of rec-ommendations for s,eci6c issues< sometimes the only a9ailable e9idence as Eudged

to be of lo @uality" While se9en @uestions are the focus of this fourth edition+ ad-ditional @uestions emerged"

Ga,s in the e9idence and additional @uestions are summari1ed belo as suggestionsfor future research" * fe may be amenable to systematic re9ies+ but others illre@uire clinical trials+ large cohort studies+ e,idemiological studies+ or beha9ioural

research" The suggestions are listed 5in no order of ,riority8 under each of the se9en@uestions"

1. duration o! ri!am*icin in 'I(&negative " *atients

XFor 9arious forms of drug resisXance 5oXher Xhan $D?8+ and balanced againsX Xol-erability and costs+ hat is the minimum number of eecti9e drugs for the inten-

si9e and continuation ,hases

X0n ,arXicular counXries folloed ,ros,ecXi9ely+ haX is Xhe cosX and im,acX of changing from a 7H to a !H? continuation ,hase

X0n ne cases of T% meningiXis 5and oXher forms of eAXra,ulmonary T%8+ haX isthe o,timal duration of treatment

2. I ntermittent dosing

X0n ne ,ulmonary T% ,aXienXs+ does daily XreaXmenX XhroughouX Xhe course of thera,y+ com,ared ith a tice ee=ly or times ee=ly intermittent regimenthroughout the course of thera,y+ reduce rela,se+ failure and ac@uired drug resis-

tance

XWhaX is Xhe im,acX of drug resisXance on ouXcomes aer inXermiXXenX regimens

XWhaX is Xhe im,acX on adherence of Xhree Ximes ee=ly dosing+ for eAam,le hen,ro9ided by a family member after a daily intensi9e ,hase

XHo im,orXanX is earlier culXure con9ersion 5associaXed iXh a daily inXensi9e

,hase8 to ,atient outcomes and T% transmission



1% 2


3. reatment o! ne/ *atients /here isoniaid resistance is high

X0n ne ,aXienXs iXh smear-,osiXi9e ,ulmonary T%+ does H? in Xhe conXinuaXion,hase for ! months reduce failure+ rela,se and ac@uired drug resistance com,ared

ith H?XWhaX is Xhe ecacy of eXhambuXol in ,re9enXing ac@uisiXion of rifam,icin resis-

tance in ,atients ith ,retreatment isonia1id resistance

XWhaX oXher ecacious and Xolerable regimens eAisX for isonia1id-resisXanX T%

XWhaX is Xhe incidence of ocular XoAiciXy due Xo eXhambuXol

XDo ne ,aXienXs iXh isonia1id resisXance res,ond dierenXly from ,re9iouslytreated ,atients ith the same drug resistance ,ro6le

%. ' I(&re#ated "

X0n ne H0-,osiXi9e ,aXienXs iXh smear-,osiXi9e ,ulmonary T% ho are gi9en*?T+ does a (-month rifam,icin-based T% treatment regimen+ com,ared ith a

7-month rifam,icin-based regimen+ increase treatment success rate and reducerecurrent T% at the end of treatment and for the 6rst )& months after successful

com,letion of treatment

X0n ,aXienXs on *?T+ haX is Xhe im,acX of Xhree Ximes ee=ly XreaXmenX com,ared

ith daily treatment during the continuation ,hase on mortality+ failure+ rela,seand ac@uired drug resistance

5. S *utum monitoring

XMsing daXa from Mnion 2Xudy * and C+ deXermine ho ell ,osiXi9e bacXeriologi-cal results at 9arious months of treatment ,redict failure and rela,se+ com,ared

ith negati9e bacteriological results"

X?eanalyse daXa from Xhe %riXish $edical ?esearch Council Xo sXudy ,aXienXs ho

are smear-,ositi9e during & consecuti9e months" Of those ,atients ho are smear-,ositi9e at & months+ ho many are still smear-,ositi9e at months Of these+

ho many are culture-,ositi9e What is the ability to ,redict treatment outcomes5?e,eat ith other ,airs of months"8

XHo ell can s,uXum moniXoring ,redicX ,reXreaXmenX or ac@uired $D?-T%

XHo useful is Xhe moniXoring of smear con9ersion as an indicaXor of T% conXrol,rogramme ,erformance

XHo oen does ,ersisXenX smear-,osiXi9iXy aX Xhe second monXh of XreaXmenX Xrig-ger ,atient or ,rogrammatic inter9entions



1% 3

annEx 5. Su$$ESIonS !or !uurE rESEarC'

). E xtension o! treatment

XFor ,re9enXing rela,se+ hich ,aXienXs sXand Xo beneX mosX from XreaXmenX eA-tension Other than ,ositi9e smear microsco,y+ hat ris= factors 5such as ,atient

eight8 ,redict ,oor outcomes+ and can feasibly be ascertained in resource-limitedsettings

X2hould Xhe inXensi9e ,hase or Xhe conXinuaXion ,hase be eAXended+ by ho long+and ith hich drugs

X0n adulXs iXh ,ulmonary T%+ does ,erforming smear microsco,y aX Xhe end of the intensi9e ,hase and+ if s,utum is smear-,ositi9e+ eAtending this ,hase reduce

failure+ rela,se or ac@uired drug resistance

+. revious#y treated *atientsX0n ne smear-,osiXi9e ,ulmonary T% ,aXienXs ho ha9e failed rsX-line T% XreaX-ment does an em,irical $D?-T% regimen+ com,ared ith the standard WHOretreatment regimen ith 6rst-line drugs+ increase treatment success rate and re-

duce failure at the end of this second course of T% treatment

XWhaX is Xhe le9el of $D? in subgrou,s of ,re9iously XreaXed ,aXienXs 5failed rsX9s" subse@uent course of thera,y< returned after defaulting< rela,sed8



1% 5

a)

$embers of the Guidelines Grou,5Technical de9elo,ment Grou,8

;olange >a!alcante

T% Control Program Coordinator+ ?io de aneiro $unici,ality+ *lmirante*leAandrino 34' %loco '&+ 2anta Tere1a ce,+ &'&!)-&7& ?io de aneiro+ ?+

%ra1il

Aeremiah =uhwa >haaya >hairperson

Technical A,ert+ .ational Le,rosy and T% Programme+ Nenya $edical ?esearch0nstitute+ PO %oA &'34)+ ''&'& .airobi+ Nenya

;aidi =. &gwaga

Programme $anager+ .ational T% and Le,rosy Programme+ $inistry of Healthand 2ocial Welfare+ P"O" %oA ('4+ Dar es 2alaam+ Mnited ?e,ublic of Tan1ania

Ro)ert @ie

Professor of $edicine+ De,artment of Paediatrics ^ Child Health+ Mni9ersity of 2tellenbosch+ Faculty of $edicine+ PO %oA )('7+ 3/'/ Tygerberg+ 2outh *frica

?eter @ondrieAecuti9e Director+ N.C Tuberculosis Foundation+ PO %oA )!7+ Par=straat )35Hofstaete %uilding8+ &/') CC The Hague+ .etherlands

-nthony :. Harries

2enior Consultant+ 0nternational Mnion *gainst Tuberculosis and Lung Disease+Old 0nn Cottage+ ears Lane+ Colden Common+ Winchester+ Hants+ ngland

?hillip Hopewell

Professor of $edicine+ Di9ision of Pulmonary ^ Critical Care+ 2an FranciscoGeneral Hos,ital+ %uilding .H+ 2FGH ?m /H/+ Mni9ersity of California 2anFrancisco 5MC2F8+ 2an Francisco+ C* (!)!-'4!)+ M2*

lessina Bumar

Flat %-)+ La=e9ie *,artment+ Plot 447+ Ward 4+ $ehrauli+ .e Delhi ))'''+0ndia

Bitty Cam)regts,!an Weezen)ec

2enior Consultant+ N.C Tuberculosis Foundation+ PO %oA )!7+ Par=straat )35Hofstaete %uilding8+ &/') CC The Hague+ .etherlands



1% )


;undari =ase

Di9ision of T% limination .ational Centre for H0+ 2TD and T%+ Centers forDisease Control and Pre9ention+ )7'' Clifton ?oad .+ $2 -)' Cor,orate 2@uare

%uilding+ %ldg )'+ *tlanta+ G* '+ M2*

Richard =enzies

Director+ ?es,iratory Di9ision+ $MHC and $cGill Mni9ersity+ ?oom N)"&!+$ontreal Chest 0nstitute+ 7/' 2t Mrbain 2treet+ $ontreal+ PI+ Canada

-nna Naanwagi =uwaya

Chief of Party+ T%C*P Program+ 0nternational Mnion *gainst Tuberculosis andLung Disease+ Plot & Loudel ?oad+ .a=asero+ PO %OJ )7'(!+ Wandegeya+ Mganda

=ahshid Nasehi

.ational T% Programme $anager+ Centre for Disease Control ^ Pre9ention+$inistry of Health and $edical ducation+ 74 0ranshahr 2treet+ Ferdosi 2@uare+))!! Tehran+ 0slamic ?e,ublic of 0ran

-ndrew Nunn

Professor of ,idemiology+ *ssociate Director+ $?C Clinical Trials Mnit+ &&&uston ?oad+ London .W) &D*+ ngland

=adhuar ?ai

*ssistant Professor+ De,artment of ,idemiology+ %iostatistics ^ Occu,ational

Health+ $cGill Mni9ersity+ )'&' Pine *9enue West+ $ontreal+ PI H* )*&+ Canada

Holger ;chDnemann

$ethodologist+ Chair+ $c$aster Mni9ersity $edical Centre+ Clinical ,idemiologyand %iostatistics+ Health 2ciences Centre &C)'%+ )&'' W" $ain 2treet+ Hamilton+

O. L4. K/+ Canada

%arir 7. Edwadia

Pri9ate Practitioner and Consultant Physician+ HinduEa Hos,ital and ?esearchCentre+ $umbai+ 0ndia

-ndrew 5ernon

Di9ision of T% limination+ .ational Centre for H0+ 2TD and T%+ Centers forDisease Control and Pre9ention+ )7'' Clifton ?oad .+ $2 -)' Cor,orate 2@uare

%uilding+ %uilding )'+ *tlanta+ G* '+ M2*

Rozalind @. 5ianzon

.ational T% Programme $anager+ .ational Center for Disease Control andPre9ention+ De,artment of Health+ !th Floor+ %uilding )+ 2an La1aro Com,ound+

2anta Cru1+ $anila+ Phili,,ines5irginia Williams

T% ProEect Director+ 0nternational Council of .urses+ Gardeners %arn+ Coc= ?oad+ye+ 2uol= 0P& 3.2+ ngland



1%+

annEx ). mEm"ErS o! 'E$uIdE#InES$rou 8EC'nICa# dE(E#omEn $rou

Externa# revie/ $rou*

Olayide *=anni+ .igeria$argareth Pretti Dalcolmo+ %ra1il

Francis Drobnies=i+ Mnited NingdomPaula FuEiara+ M2*2almaan Nesha9Eee+ M2*G"?" Nhatri+ 0ndia$ichail Perelman+ ?ussian FederationCharles 2andy+ KimbabePedro Guillermo 2uare1+ Peru$arie=e 9an der Werf+ .etherlandsWang LiAia+ China

.adia Wie=o+ 0ndonesia

$ohamed *bdel *1i1+ The Global Fund to Fight *0D2+ Tuberculosis and $alariaDaniel Nibuga+ WHO ?egional OSce for *fricaGiam,aolo $e11abotta+ WHO iet .am

amhoih Tonsing+ Family Health 0nternational Cambodia?ichard Kales=is+ WHO ?egional OSce for uro,e



Sto* ?e*artmentCorld Health rganiation28 Avenue Appia! -2--$Reneva$2;! Switerland

Ceb site+ www(who(int1tb

Jnformation ?esource Dentre HT@1STB+ tbdocsUwho(int

tuberculosis guidelines.doc

Documents